Asunto(s)

Infecciones Bacterianas , Inmunidad Innata , Humanos , Infecciones Bacterianas/inmunología , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Animales , Familia de Multigenes

RESUMEN

Mulibrey Nanism is a rare genetic disorder characterized by a variety of systemic manifestations, including cardiac involvement. We report the case of a 26-year-old male who underwent partial pericardiectomy for constrictive pericarditis at age 4 and presented to our cardiology clinic with heart failure symptoms. Examination revealed dysmorphic features characteristic of Mulibrey Nanism such as short stature, macrocephaly, and hypertelorism. Genetic testing identified a homozygous likely pathogenic mutation in the TRIM37 gene. The patient's heart failure was managed through a multidisciplinary approach, involving consultations with various specialties to address and diagnose the syndrome's complex multisystem pathologies. This case underscores the importance of including Mulibrey Nanism in the differential diagnosis of patients with a history of constrictive pericarditis at an early age and dysmorphic features, as well as the necessity of a multidisciplinary approach to manage the diverse manifestations of this rare genetic disorder.

Asunto(s)

Insuficiencia Cardíaca , Enanismo Mulibrey , Humanos , Masculino , Enanismo Mulibrey/diagnóstico , Adulto , Ubiquitina-Proteína Ligasas/genética , Proteínas de Motivos Tripartitos , Diagnóstico Diferencial

RESUMEN

Rationale: An impairment of plasma membrane repair has been implicated in various diseases such as muscular dystrophy and ischemia/reperfusion injury. MOTS-c, a short peptide encoded by mitochondria, has been shown to pass through the plasma membrane into the bloodstream. This study determined whether this biological behavior was involved in membrane repair and its underlying mechanism. Methods and Results: In human participants, the level of MOTS-c was positively correlated with the abundance of mitochondria, and the membrane repair molecule TRIM72. In contrast to high-intensity eccentric exercise, moderate-intensity exercise improved sarcolemma integrity and physical performance, accompanied by an increase of mitochondria beneath the damaged sarcolemma and secretion of MOTS-c. Furthermore, moderate-intensity exercise increased the interaction between MOTS-c and TRIM72, and MOTS-c facilitated the trafficking of TRIM72 to the sarcolemma. In vitro studies demonstrated that MOTS-c attenuated membrane damage induced by hypotonic solution, which could be blocked by siRNA-TRIM72, but not AMPK inhibitor. Co-immunoprecipitation study showed that MOTS-c interacted with TRIM72 C-terminus, but not N-terminus. The dynamic membrane repair assay revealed that MOTS-c boosted the trafficking of TRIM72 to the injured membrane. However, MOTS-c itself had negligible effects on membrane repair, which was recapitulated in TRIM72-/- mice. Unexpectedly, MOTS-c still increased the fusion of vesicles with the membrane in TRIM72-/- mice, and dot blot analysis revealed an interaction between MOTS-c and phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2]. Finally, MOTS-c blunted ischemia/reperfusion-induced membrane disruption, and preserved heart function. Conclusions: MOTS-c/TRIM72-mediated membrane integrity improvement participates in mitochondria-triggered membrane repair. An interaction between MOTS-c and plasma lipid contributes to the fusion of vesicles with membrane. Our data provide a novel therapeutic strategy for rescuing organ function by facilitating membrane repair with MOTS-c.

Asunto(s)

Membrana Celular , Mitocondrias , Sarcolema , Animales , Humanos , Ratones , Membrana Celular/metabolismo , Masculino , Mitocondrias/metabolismo , Sarcolema/metabolismo , Transporte de Proteínas , Proteínas Mitocondriales/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Adulto , Ejercicio Físico/fisiología , Ratones Noqueados , Femenino , Proteínas Portadoras/metabolismo , Proteínas de la Membrana

RESUMEN

Rationale: Tumor cells remodel transcriptome to construct an ecosystem with stemness features, which maintains tumor growth and highly malignant characteristics. However, the core regulatory factors involved in this process still need to be further discovered. Methods: Single cell RNA-sequncing (scRNA-seq) and bulk RNA-sequencing profiles derived from fetal liver, normal liver, liver tumors, and their adjacent samples were collected to analyze the ecosystem of liver cancer. Mouse models were established to identify molecular functions of oncofetal-related oncogenes using hydrodynamic tail vein injection. Results: We found that liver cancer rebuilt oncofetal ecosystem to maintain malignant features. Interestingly, we identified a group of RNA-binding proteins (RBPs) that were highly overexpressed with oncofetal features. Among them, TRIM71 was specifically expressed in liver cancers and was associated with poor outcomes. TRIM71 drove the carcinogenesis of hepatocellular carcinoma (HCC), and knockdown of TRIM71 significantly abolished liver cancer cell proliferation. Mechanistically, TRIM71 formed a protein complex with IGF2BP1, bound to and stabilized the mRNA of CEBPA in an m6A-dependent manner, enhance the serine/glycine metabolic pathway, and ultimately promoted liver cancer progression. Furthermore, we identified that all-trans-retinoic acid (ATRA) combined with e1A binding protein p300 (EP300) inhibitor A-485 repressed TRIM71, attenuated glycine/serine metabolism, and inhibited liver cancer cell proliferation with high TRIM71 levels. Conclusions: We demonstrated the oncofetal status in liver cancer and highlighted the crucial role of TRIM71 and provided potential therapeutic strategies and liver cancer-specific biomarker for liver cancer patients.

Asunto(s)

Carcinogénesis , Carcinoma Hepatocelular , Glicina , Neoplasias Hepáticas , Serina , Animales , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones , Humanos , Serina/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Glicina/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratones Desnudos

RESUMEN

BACKGROUND: Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored. METHODS: The mouse model of IRI-AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation-mass spectrometry was performed to identify potential ANKRD1-interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques. RESULTS: First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno-associated virus (rAAV9)-mitigated ischaemia/reperfusion-induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti-ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post-translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63-linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury. CONCLUSIONS: Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI-AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI. KEY POINTS/HIGHLIGHTS: Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro. ANKRD1 knockdown mitigates kidney damage and preserves renal function. Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI. ANKRD1 promotes acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway. The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1-mediated ubiquitination of ACSL3.

Asunto(s)

Daño por Reperfusión , Proteínas Represoras , Ubiquitinación , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Ratones , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Humanos , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Masculino , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Modelos Animales de Enfermedad , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Ratones Endogámicos C57BL , Riñón/metabolismo , Riñón/irrigación sanguínea , Proteínas Nucleares

RESUMEN

AIMS: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that affects the hepatic bile ducts, leading to hepatic inflammation and fibrosis. PSC can also impact skeletal muscle through the muscle-liver axis, resulting in sarcopenia, a complication characterized by a generalized loss of muscle mass and strength. The underlying mechanisms and therapy of PSC-induced sarcopenia are not well understood, but one potential regulator is the transcription factor forkhead box protein O1 (FOXO1), which is involved in the ubiquitin proteasome system. Thus, the aim of this study is to assess the pharmacological potential of FOXO1 inhibition for treating PSC-induced sarcopenia. MATERIALS AND METHODS: To establish diet-induced PSC model, we provided mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. Mice were intramuscularly injected with AS1842856 (AS), a FOXO1 inhibitor, at a dose of 3.5 mg/kg twice a week for last two weeks. C2C12 myotubes with cholic acid (CA) or deoxycholic acid (DCA) were treated with AS. KEY FINDINGS: We observed a decrease in muscle size and performance in DDC-fed mice with upregulated expression of FOXO1 and E3 ligases such as ATROGIN1 and MuRF1. We found that myotube diameter and MyHC protein level were decreased by CA or DCA in C2C12 myotubes, but treatment of AS reversed these reductions. We observed that intramuscular injection of AS effectively mitigates DDC diet-induced sarcopenia in a rodent PSC model. SIGNIFICANCE: Our study suggests that a FOXO1 inhibitor could be a potential leading therapeutic drug for relieving PSC-induced sarcopenia.

Asunto(s)

Colangitis Esclerosante , Modelos Animales de Enfermedad , Proteína Forkhead Box O1 , Sarcopenia , Transducción de Señal , Animales , Sarcopenia/metabolismo , Sarcopenia/etiología , Sarcopenia/tratamiento farmacológico , Sarcopenia/prevención & control , Sarcopenia/patología , Ratones , Proteína Forkhead Box O1/metabolismo , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/metabolismo , Colangitis Esclerosante/patología , Transducción de Señal/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Proteínas Musculares/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Piridinas/farmacología , Quinolonas

RESUMEN

TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.

Asunto(s)

Mieloma Múltiple , Complejo de la Endopetidasa Proteasomal , Proteínas de Motivos Tripartitos , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/genética , Humanos , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Pronóstico , Línea Celular Tumoral , Complejo de la Endopetidasa Proteasomal/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Autofagia/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Inhibidores de Proteasoma/farmacología , Resistencia a Antineoplásicos/genética , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Regulación Neoplásica de la Expresión Génica

RESUMEN

BACKGROUND: Colorectal cancer ranks among the most prevalent malignancies globally. Accurate prediction of metachronous liver metastasis is crucial for optimizing postoperative management. Tripartite motif-containing protein 27 (TRIM27), an E3 ubiquitin ligase, is implicated in diverse cellular functions and tumorigenesis. METHODS: This study aimed to develop and validate a TRIM27-based nomogram for prognostication in colorectal cancer patients. Transcriptome sequencing of five paired tumor and normal tissue samples identified TRIM27 as a potential prognostic biomarker. Immunohistochemistry was employed to assess TRIM27 expression in colorectal cancer cohorts from two institutions. RESULTS: TRIM27 expression correlated significantly with both the prognosis of colorectal cancer patients and the occurrence of metachronous liver metastasis. A nomogram incorporating TRIM27 and clinical factors was constructed and demonstrated robust predictive accuracy in an independent validation cohort. CONCLUSION: The TRIM27-based nomogram is a valuable prognostic tool for predicting prognosis and metachronous liver metastasis in colorectal cancer patients, aiding in personalized treatment decisions.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Colorrectales , Neoplasias Hepáticas , Nomogramas , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Anciano , Periodo Posoperatorio , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/genética , Proteínas de Motivos Tripartitos , Proteínas de Unión al ADN , Proteínas Nucleares

RESUMEN

Background: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities. Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37. Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability. Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.

Asunto(s)

Ferroptosis , Glutatión , Ácido Hialurónico , Nanopartículas , Terapia Fototérmica , ARN Interferente Pequeño , Taninos , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Humanos , Ferroptosis/efectos de los fármacos , Glutatión/metabolismo , Glutatión/química , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Taninos/química , Taninos/farmacología , Nanopartículas/química , Ácido Hialurónico/química , Femenino , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/genética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/genética , Terapia Fototérmica/métodos , Fluorocarburos/química , Fluorocarburos/farmacología , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Terapia Genética/métodos , Terapia Combinada/métodos , Animales , Hierro/química , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/metabolismo

RESUMEN

Initial studies using bioinformatics analysis revealed DNA sequence similarities between Trypanosoma cruzi GenBank® M21331, coding for Antigen 36 (Ag 36), and tripartite motif (TRIM) genes. TRIM40 showed 9.7% identity to GenBank M21331, and four additional TRIM genes had identities greater than 5.0%. TRIM37 showed a continuous stretch of identity of 12 nucleotides, that is, at least 25% longer than any of the other TRIMs. When we extended our analysis on the relationships of GenBank M21331 to further innate immune genes, using the Needleman-Wunsch (NW) algorithm for alignment, identities to human IFN-α, IFN-ß, and IFN-γ genes of 13.6%, 12.6%, and 17.9%, respectively, were found. To determine the minimum number of genes coding for proteins closely related to Ag 36, a BLAST-p search was conducted with it versus the T. cruzi genome. The BLAST-p search revealed that T. cruzi GenBank M21331 had 14 gene sequences homologous to microtubule-associated protein (MAP) genes with 100% amino acid sequence identity. To verify the similarities in non-human genes, a study comparing TRIM21 region sequences among mammalian species to the comparable human TRIM21 region showed that related sequences were also present in 11 mammalian species. The MAP genes homologous to Ag 36 form a family of at least 14 genes which mimic human immune genes in the IFN and TRIM families. This mimicry is of gene sequences and not their protein products or epitopes. These results appear to be the first description of molecular mimicry of immune genes in humans by a protozoan parasite.

Asunto(s)

Trypanosoma cruzi , Trypanosoma cruzi/genética , Trypanosoma cruzi/inmunología , Humanos , Animales , Proteínas Protozoarias/genética , Interferones/genética , Biología Computacional , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Proteínas de Motivos Tripartitos/genética

RESUMEN

Acquired myasthenia (AM), a debilitating autoimmune disease, is typically characterized by skeletal muscle fatigue and weakness. Despite advances in myasthenia gravis treatment, current approaches remain unsatisfactory and many result in unexpected side effects. Traditional Chinese medicine has shown great potential in the treatment of myasthenia gravis, including relieving myasthenic symptoms, improving patients' quality of life, and reducing Western medicine side effects. This study investigates the protective effects and mechanism of BZYQD in mice with acquired myasthenia. BZYQD alleviates the reduced grip strength and increased expression of MAFbx and MuRF-1 in mice with acquired myasthenia. It also reduces levels of pro-inflammatory factors IL-1ß, IL-6, and TNF-α in the mouse serum. In addition, BZYQD reduces ROS accumulation and the mitochondrial ROS production rate, while increasing ATP levels and mitochondrial membrane potential in mice with acquired myasthenia. Moreover, BZYQD decreases the expression of p-JAK2, p-STAT3, and p-AKT in the skeletal muscle of mice with acquired myasthenia. In summary, BZYQD reduces inflammation, enhances mitochondrial function, and regulates the JAK2/STAT3/AKT signaling pathway to treat acquired myasthenia.

Asunto(s)

Medicamentos Herbarios Chinos , Janus Quinasa 2 , Mitocondrias , Proteínas Proto-Oncogénicas c-akt , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/inmunología , Femenino , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Miastenia Gravis Autoinmune Experimental/tratamiento farmacológico , Miastenia Gravis Autoinmune Experimental/inmunología , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Musculares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo

RESUMEN

The multigene TRIM family is an important component of the innate immune system. For a long time, the main function of the genes belonging to this family was believed to be an antiviral defense of the host organism. The issue of their participation in the immune system response to bacterial invasion has been less studied. This review is the first comprehensive analysis of the mechanisms of functioning of the TRIM family genes in response to bacterial infections, which expands our knowledge about the role of TRIM in the innate immune system. When infected with different types of bacteria, individual TRIM proteins regulate inflammatory, interferon, and other responses of the immune system in the cells, and also affect autophagy and apoptosis. Functioning of TRIM proteins in response to bacterial infection, as well as viral infection, often includes ubiquitination and various protein-protein interactions with both bacterial proteins and host cell proteins. At the same time, some TRIM proteins, on the contrary, contribute to the infection development. Different members of the TRIM family possess similar mechanisms of response to viral and bacterial infection, and the final impact of these proteins could vary significantly. New data on the effect of TRIM proteins on bacterial infections make an important contribution to a more detailed understanding of the innate immune system functioning in animals and humans when interacting with pathogens. This data could also be used for the search of new targets for antibacterial defense.

Asunto(s)

Infecciones Bacterianas , Inmunidad Innata , Proteínas de Motivos Tripartitos , Humanos , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/genética , Animales , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Familia de Multigenes

RESUMEN

The worldwide impact of liver diseases is increasing steadily, with a consistent upswing evidenced in incidence and mortality rates. Chronic liver diseases (CLDs) refer to the liver function's progressive deterioration exceeding six months, which includes abnormal clotting factors, detoxification failure, and hepatic cholestasis. The most common etiologies of CLDs are mainly composed of chronic viral hepatitis, MAFLD/MASH, alcoholic liver disease, and genetic factors, which induce inflammation and harm to the liver, ultimately resulting in cirrhosis, the irreversible final stage of CLDs. The latest research has shown that tripartite motif family proteins (TRIMs) function as E3 ligases, which participate in the progression of CLDs by regulating gene and protein expression levels through post-translational modification. In this review, our objective is to clarify the molecular mechanisms and potential therapeutic targets of TRIMs in CLDs and provide insights for therapy guidelines and future research.

Asunto(s)

Hepatopatías , Proteínas de Motivos Tripartitos , Humanos , Hepatopatías/metabolismo , Hepatopatías/genética , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Enfermedad Crónica , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética

RESUMEN

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Asunto(s)

Virus Chikungunya , Músculo Esquelético , Atrofia Muscular , Estrés Oxidativo , Animales , Atrofia Muscular/virología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Ratones , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/virología , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Fiebre Chikungunya/metabolismo , Inflamación/patología , Inflamación/metabolismo , Inflamación/virología , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Replicación Viral , Ratones Endogámicos C57BL , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Infecciones por Alphavirus/virología , Infecciones por Alphavirus/patología , Infecciones por Alphavirus/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Modelos Animales de Enfermedad , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética

RESUMEN

Sarcopenia, a condition caused by an imbalance between muscle growth and loss, can severely affect the quality of life of elderly patients with metabolic, inflammatory, and cancer diseases. Vigeo, a nuruk-fermented extract of three plants (Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK)) has been reported to have anti-osteoporotic effects. However, evidence of the effects of Vigeo on muscle atrophy is not available. Here, in the in vivo model of dexamethasone (Dex)-induced muscle atrophy, Vigeo treatment significantly reversed Dex-induced decreases in calf muscle volume, gastrocnemius (GA) muscle weight, and histological cross-section area. In addition, in mRNA and protein analyses isolated from GA muscle, we observed that Vigeo significantly protected against Dex-induced mouse muscle atrophy by inhibiting protein degradation regulated by atrogin and MuRF-1. Moreover, we demonstrated that Vigeo significantly promoted C2C12 cell line differentiation, as evidenced by the increased width and length of myotubes, and the increased number of fused myotubes with three or more nuclei. Vigeo alleviated the formation of myotubes compared to the control group. Vigeo also significantly increased the mRNA and protein expression of myosin heavy chain (MyHC), MyoD, and myogenin compared to that in the control. Vigeo treatment significantly reduced the mRNA and protein expression of muscle degradation markers atrogin-1 and muscle RING Finger 1 (MuRF-1) in the C2C12 cell line in vitro. Vigeo also activated the AMP-activated protein kinase (AMPK)/silent information regulator 1 (Sirt-1)/peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) mitochondrial biogenesis pathway and the Akt/mTOR protein synthesis signaling pathway in Dex-induced myotube atrophy. These findings suggest that Vigeo may have protective effects against Dex-induced muscle atrophy. Therefore, we propose Vigeo as a supplement or potential therapeutic agent to prevent or treat sarcopenia accompanied by muscle atrophy and degeneration.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Diferenciación Celular , Dexametasona , Fibras Musculares Esqueléticas , Atrofia Muscular , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Sirtuina 1 , Serina-Treonina Quinasas TOR , Animales , Dexametasona/farmacología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/prevención & control , Atrofia Muscular/metabolismo , Transducción de Señal/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Diferenciación Celular/efectos de los fármacos , Sirtuina 1/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Extractos Vegetales/farmacología , Masculino , Proteolisis/efectos de los fármacos , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Línea Celular , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas de Motivos Tripartitos

RESUMEN

The different susceptibility to HIV-1 infection in U937 cells-permissive (Plus) or nonpermissive (Minus)-is linked to the expression in Minus cells of interferon (IFN)-γ inducible antiviral factors such as tripartite motif-containing protein 22 (TRIM22) and class II transactivator (CIITA). CIITA interacts with Cyclin T1, a key component of the Positive-Transcription Elongation Factor b (P-TEFb) complex needed for the efficient transcription of HIV-1 upon interaction with the viral transactivator Tat. TRIM22 interacts with CIITA, recruiting it into nuclear bodies together with Cyclin T1. A 50 kDa Cyclin T1 was found only in Minus cells, alongside the canonical 80 kDa protein. The expression of this truncated form remained unaffected by proteasome inhibitors but was reduced by IFNγ treatment. Unlike the nuclear full-length protein, truncated Cyclin T1 was also present in the cytoplasm, and this subcellular localization correlated with its capacity to inhibit Tat-mediated HIV-1 transcription. The 50 kDa Cyclin T1 in Minus cells likely contributes to their non-permissive phenotype by acting as a dominant negative factor, disrupting P-TEFb complex formation and function. Its reduction upon IFNγ treatment suggests a regulatory loop by which its inhibitory role on HIV-1 replication is then exerted by the IFNγ-induced CIITA, which binds to the canonical Cyclin T1, displacing it from the P-TEFb complex.

Asunto(s)

Ciclina T , VIH-1 , Humanos , Ciclina T/metabolismo , VIH-1/fisiología , Células U937 , Infecciones por VIH/virología , Infecciones por VIH/metabolismo , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Replicación Viral , Fenotipo , Interferón gamma/farmacología , Interferón gamma/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Antígenos de Histocompatibilidad Menor

RESUMEN

The deubiquitinase tripartite motif containing 44 (TRIM44) plays a critical role in linking the proteotoxic stress response with autophagic degradation, which is significant in the context of cancer and neurological diseases. Although TRIM44 is recognized as a prognostic marker in various cancers, the complex molecular mechanisms through which it facilitates autophagic degradation, particularly under oxidative stress conditions, have not been fully explored. In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide. Our research emphasizes the critical role of the posttranslational modification of sequestosome-1 (SQSTM1) and its importance in improving sequestration during autophagic degradation under oxidative stress. We found that TRIM44 notably promotes SQSTM1 oligomerization in both PB1 domain-dependent and oxidation-dependent manners. Furthermore, TRIM44 amplifies the interaction between protein kinase A and oligomerized SQSTM1, leading to enhanced phosphorylation of SQSTM1 at S349. This phosphorylation event activates NFE2L2, a key transcription factor in the oxidative stress response, highlighting the importance of TRIM44 in modulating SQSTM1-mediated autophagy. Our findings support that TRIM44 plays pivotal roles in regulating autophagic sensitivity to oxidative stress, with implications for cancer, aging, aging-associated diseases, and neurodegenerative disorders.

Asunto(s)

Autofagia , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Proteína Sequestosoma-1 , Proteínas de Motivos Tripartitos , Proteína Sequestosoma-1/metabolismo , Humanos , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación , Trióxido de Arsénico/farmacología , Multimerización de Proteína , Línea Celular Tumoral , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células HEK293

RESUMEN

To investigate the changes in neuronal lipid droplet (LD) accumulation and lipid metabolism after acute spinal cord injury (SCI), we established a rat model of compressive SCI. Oil Red O staining, BODIPY 493/503 staining, and 4-hydroxynonenal immunofluorescence staining were performed to determine overall LD accumulation, neuronal LD accumulation, and lipid peroxidation. Lipidomics was conducted to identify the lipid components in the local SCI microenvironment. We focused on the expression and regulation of perilipin 2 (PLIN2) and knocked down PLIN2 in vivo by intrathecal injection of adeno-associated virus 9-synapsin-short-hairpin RNA-PLIN2 (AAV9-SYN-shPlin2). Motor function was assessed using the Basso-Beattie-Bresnahan score. Proteins that interacted with PLIN2 were screened by immunoprecipitation (IP) and qualitative shotgun proteomics, and confirmed by co-IP. A ubiquitination assay was performed to validate whether ubiquitination was involved in PLIN2 degradation. Oil Red O staining indicated that LDs steadily accumulated after SCI. Fluorescent staining indicated the accumulation of LDs in neurons with increased lipid peroxidation. Lipidomics revealed significant changes in lipid components after SCI. PLIN2 expression significantly increased following SCI, and knockdown of PLIN2 using AAV9-SYN-Plin2 reduced neuronal LD accumulation. This intervention improved the neuronal survival and motor function of injured rats. IP and qualitative shotgun proteomics identified tripartite motif-containing protein 21 (TRIM21) as a direct binding protein of PLIN2, and this interaction was confirmed by co-IP in vitro and immunofluorescence staining in vivo. By manipulating TRIM21 expression, we found it was negatively correlated with PLIN2 expression. In conclusion, PLIN2 is involved in neuronal LD accumulation following SCI. TRIM21 mediated the ubiquitination and degradation of PLIN2 in neurons. Inhibition of PLIN2 enhanced the recovery of motor function after SCI.

Asunto(s)

Gotas Lipídicas , Neuronas , Perilipina-2 , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Ubiquitinación , Animales , Femenino , Masculino , Ratas , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos/fisiología , Neuronas/metabolismo , Perilipina-2/metabolismo , Perilipina-2/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética

RESUMEN

Deregulation of E3 ubiquitin ligases drives the proliferation and metastasis of various cancers; however, the underlying mechanisms remain unknown. This study aimed to investigate the role of tripartite motif-containing 22 (TRIM22), a poorly investigated E3 ubiquitin ligase in the TRIM family, as a tumor suppressor in breast cancer. High expression of TRIM22 in breast cancer correlated with better prognosis. Functional experiments demonstrated that TRIM22 significantly inhibited the proliferation and invasion of breast cancer cells. Label-free proteomics and biochemical analyses revealed that the copper chaperone for superoxide dismutase (CCS), an oncoprotein that is upregulated in breast cancer and promotes the growth and invasion of breast cancer cells, was a target of TRIM22 for degradation via K27-linked ubiquitination. Notably, the ability of the coiled-coil domain-defective mutants of TRIM22 to induce CCS ubiquitination and degradation diminished, with lysine 76 of the CCS serving as the ubiquitination site. Moreover, the TRIM22-mediated inhibition of the proliferation and invasion of breast cancer cells was restored by ectopic CCS expression. RNA-sequencing experiments using Gene Set Enrichment Analysis demonstrated that TRIM22 is involved in the JAK-STAT signaling pathway. TRIM22 overexpression also improved reactive oxygen species levels in breast cancer cells and inhibited STAT3 phosphorylation, which was restored via CCS overexpression or N-acetyl-l-cysteine treatment. Chromatin immunoprecipitation-quantitative polymerase chain reaction results showed that TRIM22 overexpression decreased the enrichment of phosphorylated STAT3 in FN1, VIM and JARID2 promoters. Clinically, low TRIM22 expression correlated with high CCS expression and decreased survival rates in patients with breast cancer. Moreover, TRIM22 upregulation was associated with a better prognosis in patients with breast cancer who received classical therapy. TRIM22 expression was downregulated in many cancer types, including colon, kidney, lung, and prostate cancers. To the best of our knowledge, the E3 ubiquitin ligase TRIM22 was first reported as a tumor suppressor that inhibits the proliferation and invasion of breast cancer cells through CCS ubiquitination and degradation. TRIM22 is a potential prognostic biomarker in patients with breast cancer.

Asunto(s)

Neoplasias de la Mama , Proliferación Celular , Antígenos de Histocompatibilidad Menor , Factor de Transcripción STAT3 , Transducción de Señal , Proteínas de Motivos Tripartitos , Ubiquitinación , Femenino , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células MCF-7 , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Invasividad Neoplásica , Pronóstico , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética

RESUMEN

Flaviviruses comprise a large number of arthropod-borne viruses, some of which are associated with life-threatening diseases. Flavivirus infections are rising worldwide, mainly due to the proliferation and geographical expansion of their vectors. The main human pathogens are mosquito-borne flaviviruses, including dengue virus, Zika virus, and West Nile virus, but tick-borne flaviviruses are also emerging. As with any viral infection, the body's first line of defense against flavivirus infections is the innate immune defense, of which type I interferon is the armed wing. This cytokine exerts its antiviral activity by triggering the synthesis of hundreds of interferon-induced genes (ISGs), whose products can prevent infection. Among the ISGs that inhibit flavivirus replication, certain tripartite motif (TRIM) proteins have been identified. Although involved in other biological processes, TRIMs constitute a large family of antiviral proteins active on a wide range of viruses. Furthermore, whereas some TRIM proteins directly block viral replication, others are positive regulators of the IFN response. Therefore, viruses have developed strategies to evade or counteract TRIM proteins, and some even hijack certain TRIM proteins to their advantage. In this review, we summarize the current state of knowledge on the interactions between flaviviruses and TRIM proteins, covering both direct and indirect antiviral mechanisms.

Asunto(s)

Infecciones por Flavivirus , Flavivirus , Replicación Viral , Humanos , Infecciones por Flavivirus/virología , Infecciones por Flavivirus/inmunología , Flavivirus/fisiología , Flavivirus/inmunología , Animales , Inmunidad Innata , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Interacciones Huésped-Patógeno/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo