RESUMEN

Proteostasis, including protein folding mediated by molecular chaperones, protein degradation, and stress response pathways in organelles like ER (unfolded protein response: UPR), are responsible for cellular protein quality control. This is essential for cell survival as it regulates and reprograms cellular processes. Here, we underscore the role of the proteostasis pathway in Apicomplexan parasites with respect to their well-characterized roles as well as potential roles in many parasite functions, including survival, multiplication, persistence, and emerging drug resistance. In addition to the diverse physiological importance of proteostasis in Apicomplexa, we assess the potential of the pathway's components as chemotherapeutic targets.

RESUMEN

In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.

RESUMEN

One of the most important questions in cell biology is how cell fate is determined when exposed to extreme stresses such as heat shock. It has been long understood that organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of denatured or unfolded proteins triggers the synthesis of heat shock proteins (HSPs) through the heat shock transcription factor, e.g., heat shock factor 1 (HSF1). In this study, a dynamical model validated with experiments is presented to analyse the role of HSF1 SUMOylation in response to heat shock. Key features of this model are inclusion of heat shock response and SUMOylation of HSF1, and HSP synthesis at molecular level, describing the dynamical evolution of the key variables involved in the regulation of HSPs. The model has been employed to predict the SUMOylation levels of HSF1 with different external temperature stimuli. The results show that the SUMOylated HSF1 levels agree closely with the experimental findings. This demonstrates the validity of this nonlinear dynamic model for the important role of SUMOylation in response to heat shock.

Asunto(s)

Proteínas de Unión al ADN , Sumoilación , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción del Choque Térmico/genética , Proteínas de Choque Térmico/genética , Respuesta al Choque Térmico

RESUMEN

Cells respond to protein-damaging (proteotoxic) stress by activation of the Heat Shock Response (HSR). The HSR provides cells with an enhanced ability to endure proteotoxic insults and plays a crucial role in determining subsequent cell death or survival. The HSR is, therefore, a critical factor that influences the toxicity of protein stress. While named for its vital role in the cellular response to heat stress, various components of the HSR system and the molecular chaperone network execute essential physiological functions as well as responses to other diverse toxic insults. The effector molecules of the HSR, the Heat Shock Factors (HSFs) and Heat Shock Proteins (HSPs), are also important regulatory targets in the progression of neurodegenerative diseases and cancers. Modulation of the HSR and/or its extended network have, therefore, become attractive treatment strategies for these diseases. Development of effective therapies will, however, require a detailed understanding of the HSR, important features of which continue to be uncovered and are yet to be completely understood. We review recently described and hallmark mechanistic principles of the HSR, the regulation and functions of HSPs, and contexts in which the HSR is activated and influences cell fate in response to various toxic conditions.

Asunto(s)

Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico/fisiología , Proteostasis/fisiología , Animales , Supervivencia Celular/fisiología , Humanos , Chaperonas Moleculares/metabolismo , Neoplasias/patología , Neoplasias/terapia , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/terapia

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is often accompanied by metabolic disorders such as metabolic syndrome and type 2 diabetes (T2DM). Heat shock response (HSR) is one of the most important homeostatic abilities but is deteriorated by chronic metabolic insults. Heat shock (HS) with an appropriate mild electrical stimulation (MES) activates HSR and improves metabolic abnormalities including insulin resistance, hyperglycemia and inflammation in metabolic disorders. To analyze the effects of HS + MES treatment on NAFLD biomarkers, three cohorts including healthy men (two times/week, n = 10), patients with metabolic syndrome (four times/week, n = 40), and patients with T2DM (n = 100; four times/week (n = 40) and two, four, seven times/week (n = 20 each)) treated with HS + MES were retrospectively analyzed. The healthy subjects showed no significant alterations in NAFLD biomarkers after the treatment. In patients with metabolic syndrome, many of the NAFLD steatosis markers, including fatty liver index, NAFLD-liver fat score, liver/spleen ratio and hepatic steatosis index and NAFLD fibrosis marker, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, were improved upon the treatment. In patients with T2DM, all investigated NAFLD steatosis markers were improved and NAFLD fibrosis markers such as the AST/ALT ratio, fibrosis-4 index and NAFLD-fibrosis score were improved upon the treatment. Thus, HS + MES, a physical intervention, may become a novel treatment strategy for NAFLD as well as metabolic disorders.

RESUMEN

Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1 transcription factor activity from cytotoxic proteostasis stress and thereby better elucidate the proposed role(s) of HSF1 in the HIV-1 lifecycle. To achieve this objective, we used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results clarify the interplay between the host's heat shock response and HIV-1 infection and motivate continued investigation of chaperones as potential antiviral therapeutic targets.

Asunto(s)

Respuesta al Choque Térmico , Proteostasis , Factores de Transcripción del Choque Térmico/genética , Factores de Transcripción del Choque Térmico/metabolismo , Humanos , Chaperonas Moleculares , Replicación Viral

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a disorder that affects motor neurons in motor cortex and spinal cord, and the degeneration of both neuronal populations is a critical feature of the disease. Abnormalities in protein homeostasis (proteostasis) are well established in ALS. However, they have been investigated mostly in spinal cord but less so in motor cortex. Herein, we monitored the unfolded protein (UPR) and heat shock response (HSR), two major proteostasis regulatory pathways, in human post-mortem tissue derived from the motor cortex of sporadic ALS (SALS) and compared them to those occurring in spinal cord. Although the UPR was activated in both tissues, specific expression of select UPR target genes, such as PDIs, was observed in motor cortex of SALS cases strongly correlating with oligodendrocyte markers. Moreover, we found that endoplasmic reticulum-associated degradation (ERAD) and HSR genes, which were activated predominately in spinal cord, correlated with the expression of neuronal markers. Our results indicate that proteostasis is strongly and selectively activated in SALS motor cortex and spinal cord where subsets of these genes are associated with specific cell type. This study expands our understanding of convergent molecular mechanisms occurring in motor cortex and spinal cord and highlights cell type-specific contributions.

Asunto(s)

Esclerosis Amiotrófica Lateral/metabolismo , Especificidad de Órganos , Proteostasis , Transducción de Señal , Respuesta de Proteína Desplegada , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Estudios de Casos y Controles , Estrés del Retículo Endoplásmico/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Regulación de la Expresión Génica , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Factores de Transcripción del Choque Térmico/metabolismo , Respuesta al Choque Térmico/genética , Humanos , Persona de Mediana Edad , Modelos Biológicos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Corteza Motora/metabolismo , Corteza Motora/patología , Neuronas Motoras/metabolismo , Especificidad de Órganos/genética , Proteína Disulfuro Isomerasas/genética , Proteína Disulfuro Isomerasas/metabolismo , Mapas de Interacción de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Respuesta de Proteína Desplegada/genética , Proteínas de Transporte Vesicular/metabolismo , Adulto Joven

RESUMEN

The heat shock response (HSR) induced by photothermal therapy (PTT), which can cause tumor cells to resist apoptosis, has increasingly attracted the attention of researchers. Synergistic treatment of tumors using multiple means to improve therapeutic efficiency would be a promising strategy for effective cancer treatment. In this study, a cancer cell membrane-camouflaged nanocarrier was developed and loaded with tellurium (Te) and cantharidin (CTD) for efficient combinatorial therapy. The designed nanoparticles (m-CTD@Te) used a 4T1 cell membrane coating as the shell with homologous targeting capability, CTD as an the HSR inhibitor and antitumor drug, and Te as a PTT and photodynamic therapy (PDT) photosensitizer. An in vivo study indicated that the tumor inhibition rate of this combinatorial therapy could reach approximately 82.3% in 4T1 mammary tumor models. This study suggested that m-CTD@Te, as a versatile biomimetic nanoplatform, provides a new alternative for more precise and effective tumor treatment. STATEMENT OF SIGNIFICANCE: In this work, we constructed cell membrane-coated biomimetic nanoparticles (m-CTD@Te) to suppress cancer effectively through synergistic treatment. The developed m-CTD@Te nanoparticles presented strong homologous targeting capabilities. The encapsulated Te triggered PDT and PPT under the near-infrared laser irradiation. Subsequently, the PTT triggered the release of CTD, which could suppress the HSR of tumor and achieve chemotherapy. In addition, due to the presence of outer cell membrane coating, these m-CTD@Te nanoparticles showed good biocompatibility to healthy cells.

Asunto(s)

Nanopartículas , Fotoquimioterapia , Biomimética , Cantaridina , Respuesta al Choque Térmico , Humanos , Fototerapia , Terapia Fototérmica , Telurio

RESUMEN

Oncogenesis involves continuous genetic alterations that lead to compromised cellular integrity and immortal cell fate. The cells remain under excessive stress due to endo- and exogenous influences. Human Satellite III long noncoding RNA (SatIII lncRNA) is a key regulator of the global cellular stress response, although its function is poorly explained in cancers. The principal regulator of cancer meshwork is tumor protein p53, which if altered may result in chemoresistance. The heat shock factor 1 (HSF1) being a common molecule between the oncogenic control and global cellular stress acts as an oncogene as well as transcribes SatIII upon heat shock. This prompted us to determine the structure of SatIII RNA and establish the association between SatIII-HSF1-p53. We determined the most stable structure of SatIII RNA with the least energy of - 115.7 kcal/mol. Also, we observed a possible interaction of p53 with SatIII and HSF1 using support vector machine (SVM) algorithm for predicting RNA-protein interaction (RPI). Further, we employ the STRING database to understand if p53 is an interacting component of the nuclear stress bodies (nSBs). A precise inference was drawn from molecular docking which confirmed the interaction of SatIII-HSF1-p53, where a mutated p53 resulted in an altered DNA-binding property with the SatIII molecule. This study being first of its kind infers p53 to be a possible integral component of the nSBs, which may regulate cellular stress response during cancer progression in the presence of HSF1 and SatIII. An extended research on the regulations of SatIII and p53 may open new avenues in the field of apoptosis in cancer and the early approach of molecular targeting.

Asunto(s)

Carcinogénesis/patología , Núcleo Celular/genética , Factores de Transcripción del Choque Térmico/metabolismo , ARN Largo no Codificante/metabolismo , Satélite de ARN/metabolismo , Estrés Fisiológico , Proteína p53 Supresora de Tumor/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Células HeLa , Factores de Transcripción del Choque Térmico/química , Factores de Transcripción del Choque Térmico/genética , Respuesta al Choque Térmico , Humanos , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Conformación Proteica , ARN Largo no Codificante/química , ARN Largo no Codificante/genética , Satélite de ARN/química , Satélite de ARN/genética , Transcripción Genética , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética

RESUMEN

The heat shock response (HSR) was originally discovered as a transcriptional response to elevated temperature shock and led to the identification of heat shock proteins and heat shock factor 1 (HSF1). Since then HSF1 has been shown to be important for combating other forms of environmental perturbations as well as genetic variations that cause proteotoxic stress. The HSR has long been thought to be an absolute response to conditions of cell stress and the primary mechanism by which HSF1 promotes organismal health by preventing protein aggregation and subsequent proteome imbalance. Accumulating evidence now shows that HSF1, the central player in the HSR, is regulated according to specific cellular requirements through cell-autonomous and non-autonomous signals, and directs transcriptional programs distinct from the HSR during development and in carcinogenesis. We discuss here these 'non-canonical' roles of HSF1, its regulation in diverse conditions of development, reproduction, metabolism, and aging, and posit that HSF1 serves to integrate diverse biological and pathological responses.

Asunto(s)

Factores de Transcripción del Choque Térmico/metabolismo , Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico , Proteoma/metabolismo , Animales , Carcinogénesis/metabolismo , Humanos , Modelos Biológicos , Agregación Patológica de Proteínas/metabolismo , Transducción de Señal

RESUMEN

Described is the role that heat shock factor 1 (HSF1) plays in regulating cellular stress. Focusing on the current state of the HSF1 field in chemotherapeutics we outline the cytoprotective role of HSF1 in the cell. Summarizing the mechanism by which HSF1 regulates the unfolded proteins that are generated under stress conditions provides the background on why HSF1, the master regulator, is such an important protein in cancer cell growth. Summarizing siRNA knockdown results and current inhibitors provides a comprehensive evaluation on HSF1 and its current state. One set of molecules stands out, in that they completely obliterate the levels of HSF1, while simultaneously inhibiting heat shock protein 90 (Hsp90). These molecules are extremely promising as chemotherapeutic agents and as tools that may ultimately provide the connection between Hsp90 inhibition and HSF1 protein levels.

Asunto(s)

Proteínas HSP90 de Choque Térmico/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Humanos

RESUMEN

Misfolded membrane proteins are retained in the endoplasmic reticulum (ER) and are subject to ER-associated degradation, which clears the secretory pathway of potentially toxic species. While the transcriptional response to environmental stressors has been extensively studied, limited data exist describing the cellular response to misfolded membrane proteins. To this end, we expressed and then compared the transcriptional profiles elicited by the synthesis of three ER retained, misfolded ion channels: The α-subunit of the epithelial sodium channel, ENaC, the cystic fibrosis transmembrane conductance regulator, CFTR, and an inwardly rectifying potassium channel, Kir2.1, which vary in their mass, membrane topologies, and quaternary structures. To examine transcriptional profiles in a null background, the proteins were expressed in yeast, which was previously used to examine the degradation requirements for each substrate. Surprisingly, the proteins failed to induce a canonical unfolded protein response or heat shock response, although messages encoding several cytosolic and ER lumenal protein folding factors rose when αENaC or CFTR was expressed. In contrast, the levels of these genes were unaltered by Kir2.1 expression; instead, the yeast iron regulon was activated. Nevertheless, a significant number of genes that respond to various environmental stressors were upregulated by all three substrates, and compared with previous microarray data we deduced the existence of a group of genes that reflect a novel misfolded membrane protein response. These data indicate that aberrant proteins in the ER elicit profound yet unique cellular responses.

Asunto(s)

Proteínas de la Membrana/genética , Saccharomyces cerevisiae/metabolismo , Estrés Fisiológico , Membrana Celular/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Canales Epiteliales de Sodio , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Ontología de Genes , Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Pliegue de Proteína , Regulón/genética , Reproducibilidad de los Resultados , Saccharomyces cerevisiae/genética , Regulación hacia Arriba/genética