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Nucleoprotein (N) is well known for its function in the encapsidation of the genomic RNAs of negative-strand RNA viruses, which leads to the formation of ribonucleoproteins that serve as templates for viral transcription and replication. However, the function of the N protein in other aspects during viral infection is far from clear. In this study, the N protein of snakehead vesiculovirus (SHVV), a kind of fish rhabdovirus, was proved to be ubiquitinated mainly via K63-linked ubiquitination. We identified nine host E3 ubiquitin ligases that interacted with SHVV N, among which seven E3 ubiquitin ligases facilitated ubiquitination of the N protein. Further investigation revealed that only two E3 ubiquitin ligases, Siah E3 ubiquitin protein ligase 2 (Siah2) and leucine-rich repeat and sterile alpha motif containing 1 (LRSAM1), mediated K63-linked ubiquitination of the N protein. SHVV infection upregulated the expression of Siah2 and LRSAM1, which maintained the stability of SHVV N. Besides, overexpression of Siah2 or LRSAM1 promoted SHVV replication, while knockdown of Siah2 or LRSAM1 inhibited SHVV replication. Deletion of the ligase domain of Siah2 or LRSAM1 did not affect their interactions with SHVV N but reduced the K63-linked ubiquitination of SHVV N and SHVV replication. In summary, Siah2 and LRSAM1 mediate K63-linked ubiquitination of SHVV N to facilitate SHVV replication, which provides novel insights into the role of the N proteins of negative-strand RNA viruses. IMPORTANCE: Ubiquitination of viral protein plays an important role in viral replication. However, the ubiquitination of the nucleoprotein (N) of negative-strand RNA viruses has rarely been investigated. This study aimed at investigating the ubiquitination of the N protein of a fish rhabdovirus SHVV (snakehead vesiculovirus), identifying the related host E3 ubiquitin ligases, and determining the role of SHVV N ubiquitination and host E3 ubiquitin ligases in viral replication. We found that SHVV N was ubiquitinated mainly via K63-linked ubiquitination, which was mediated by host E3 ubiquitin ligases Siah2 (Siah E3 ubiquitin protein ligase 2) and LRSAM1 (leucine-rich repeat and sterile alpha motif containing 1). The data suggested that Siah2 and LRSAM1 were hijacked by SHVV to ubiquitinate the N protein for viral replication, which exhibited novel anti-SHVV targets for drug design.

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The extracts of Corydalis heterocarpa, a salt-tolerant plant, exhibit diverse physiological properties, including anti-inflammatory, anticancer, and antiadipogenic effects. However, the anti-aging effects of C. heterocarpa extract (CHE) on human skin cells have not yet been investigated. In the present study, we determined that CHE inhibited senescence-associated ß-galactosidase (SA-ß-gal)-stained senescent human dermal fibroblasts (HDFs). Furthermore, CHE markedly suppressed the expression of major regulatory proteins involved in senescence, including p53, p21, and caveolin-1. Interestingly, CHE promoted autophagic flux, as confirmed by the formation of microtubule-associated protein 1 light chain 3B (LC3B) puncta and lysosomal activity. Notably, using RNA sequencing (RNA-seq), we showed that CHE selectively regulated the gene expression of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), an important regulator of autophagy. The adenosine-monophosphate activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway, which is essential for autophagy regulation, was also modulated by CHE. LRSAM1 depletion not only inhibited LC3B expression but also decreased the autophagy flux induced by CHE. Moreover, the knockdown of LRSAM1 suppressed the reversal of CHE-induced senescence in old HDFs. Collectively, our study has revealed the rejuvenating effects and molecular mechanisms of CHE, suggesting that CHE may be a promising anti-aging agent.

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Charcot-Marie-Tooth disease type 2P (CMT2P; MIM #614436) is a specific type of axonal neuropathy caused by mutations in the LRSAM1 gene, which is a RING-type E3 ubiquitin ligase. CMT2P can be inherited in two ways: as an autosomal dominant or autosomal recessive trait. In this report, we describe the clinical characteristics of a family with axonal sensory-motor neuropathy caused by a new variant of the LSRAM1 gene, which is associated with early-onset autosomal dominant CMT2P.

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BACKGROUND: Currently, there are no specific drugs or targets available for the treatment of tendinopathy. However, inflammation has recently been found to play a pivotal role in tendinopathy progression, thereby identifying it as a potential therapeutic target. Carpaine (CA) exhibits potential anti-inflammatory pharmacological properties and may offer a therapeutic option for tendinopathy. PURPOSE: This study aimed to investigate the effectiveness of CA in addressing tendinopathy and uncovering its underlying mechanisms. METHODS: Herein, the efficacy of CA by local administration in vivo in comparison to the first-line drug indomethacin was evaluated in a mouse collagenase-induced tendinopathy (CIT) model. Furthermore, IL-1ß induced a simulated pathological inflammatory microenvironment in tenocytes to investigate its underlying mechanisms in vitro. Further confirmation experiments were performed by overexpressing or knocking down the selective targets of CA in vivo. RESULTS: The findings demonstrated that CA was dose-dependent in treating tendinopathy and that the high-dose group outperformed the first-line drug indomethacin. Mechanistically, CA selectively bound to and enhanced the activity of the E3 ubiquitin ligase LRSAM1 in tendinopathy. This effect mediated the ubiquitination of p65 at lysine 93, subsequently promoting its proteasomal degradation. As a result, the NF-κB pathway was inactivated, leading to a reduction in inflammation of tendinopathy. Consequently, CA effectively mitigated the progression of tendinopathy. Moreover, the LRSAM1 overexpression demonstrated effectiveness in mitigating the tendinopathy progression and its knockdown abolished the therapeutic effects of CA. CONCLUSION: CA attenuates the progression of tendinopathy by promoting the ubiquitin-proteasomal degradation of p65 via increasing the enzyme activity of LRSAM1. The exploration of LRSAM1 has also unveiled a new potential target for treating tendinopathy based on the ubiquitin-proteasomal pathway.

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BACKGROUND/AIMS: Cells require regular maintenance of proteostasis. Synthesis of new polypeptides and elimination of damaged or old proteins is an uninterrupted mechanism essential for a healthy cellular environment. Impairment in the removal of misfolded proteins can disturb proteostasis; such toxic aggregation of misfolded proteins can act as a primary risk factor for neurodegenerative diseases and imperfect ageing. The critical challenge is to design effective protein quality control (PQC) based molecular tactics that could potentially eliminate aggregation-prone protein load from the cell. Still, targeting specific components of the PQC pathway for the suppression of proteotoxic insults retains several challenges. Earlier, we had observed that LRSAM1 promotes the degradation of aberrant proteins. Here, we examined the effect of resveratrol, a stilbenoid phytoalexin compound, treatment on LRSAM1 E3 ubiquitin ligase, involved in the spongiform neurodegeneration. METHODS: In this study, we reported induction of mRNA and protein levels of LRSAM1 in response to resveratrol treatment via RT-PCR, immunoblotting, and immunofluorescence analysis. The LRSAM1-mediated proteasomal-based clearance of misfolded proteins was also investigated via proteasome activity assays, immunoblotting and immunofluorescence analysis. The increased stability of LRSAM1 by resveratrol was demonstrated by cycloheximide chase analysis. RESULTS: Here, we show that resveratrol treatment induces LRSAM1 E3 ubiquitin ligase expression levels. Further, our findings suggest that overexpression of LRSAM1 significantly elevates proteasome activities and improves the degradation of bona fide heat-denatured luciferase protein. Exposure of resveratrol not only slows down the turnover of LRSAM1 but also effectively degrades abnormal proteinaceous inclusions, which eventually promotes cell viability. CONCLUSION: Our findings suggest that resveratrol facilitates LRSAM1 endogenous establishment, which consequently promotes the proteasome machinery for effective removal of intracellular accumulated misfolded or proteasomal-designated substrates. Altogether, our study proposes a promising molecular approach to specifically trigger PQC signaling for efficacious rejuvenation of defective proteostasis via activation of overburdened proteolytic machinery.

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In the past decade, mutations in LRSAM1 were identified as the genetic cause of both dominant and recessive forms of axonal CMT type 2P (CMT2P). Despite demonstrating different inheritance patterns, dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life. Asymptomatic individuals were identified in several pedigrees exemplifying the strong phenotypic variability of these patients requiring serial clinical evaluation to establish correct diagnosis; in this respect, magnetic resonance imaging of lower-limb musculature showing fatty atrophy might be helpful in detecting subclinical gene mutation carriers. LRSAM1 is a universally expressed RING-type E3 ubiquitin protein ligase catalysing the final step in the ubiquitination cascade. Strikingly, TSG101 remains the only known ubiquitination target hampering our mechanistic understanding of the role of LRSAM1 in the cell. The recessive CMT mutations lead to complete loss of LRSAM1, contrary to the heterozygous dominant variants. These tightly cluster in the C-terminal RING domain highlighting its importance in governing the CMT disease. The domain is crucial for the ubiquitination function of LRSAM1 and CMT mutations disrupt its function, however it remains unknown how this leads to the peripheral neuropathy. Additionally, recent studies have linked LRSAM1 with other neurodegenerative diseases of peripheral and central nervous systems. In this review we share our experience with the challenging clinical diagnosis of CMT2P and summarize the mechanistic insights about the LRSAM1 dysfunction that might be helpful for the neurodegenerative field at large.

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Numerous proteins participate and actively contribute to the various cellular mechanisms, where several of them are crucial for regular metabolism, including survival. Thus, to maintain optimal cellular physiology, cells govern protein quality control functions with the assistance of comprehensive actions of molecular chaperones, the ubiquitin-proteasome system, and autophagy. In the ubiquitin-proteasome pathway, few quality control E3 ubiquitin ligases actively participate against misfolded protein aggregation generated via stress conditions. But how these quality control E3s active expression levels returned to basal levels when cells achieved re-establishment of proteostasis is still poorly understood. Our current study demonstrated that LRSAM1 E3 ubiquitin ligase promotes the proteasomal degradation of quality control E3 ubiquitin ligase E6-AP. We have observed the co-localization and recruitment of LRSAM1 with E6-AP protein and noticed that LRSAM1 induces the endogenous turnover of E6-AP. Partial depletion of LRSAM1 elevates the levels of E6-AP and affects overall cell cycle regulatory proteins (p53 and p27) expression, including the rate of cellular proliferation. The current finding also provides an excellent opportunity to better understand the basis of the E6-AP associated pathomechanism of Angelman Syndrome disorder. Additionally, this study touches upon the novel potential molecular strategy to regulate the levels of one quality control E3 ubiquitin ligase with another E3 ubiquitin ligase and restore proteostasis and provide a possible therapeutic approach against abnormal protein aggregation diseases.

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Accumulation of aberrant misfolded proteins is a major hallmark of several neurodegenerative diseases. Intracellular accumulations of such abnormal proteins are selectively cleared by the ubiquitin-proteasome system (UPS). But how the failure of misfolded protein degradation cause proteinopathies is still an unanswered question?. Previous studies have suggested that few selective quality control (QC) E3 ubiquitin ligase from the UPS can selectively target insoluble aggregated proteins for their intracellular degradation. Few reports suggest that lack or aberrant functions of QC E3 ubiquitin ligases can be a possible causative factor of neurodegeneration and aging. Earlier findings indicated that leucine-rich repeat and sterile alpha motif containing-1 (LRSAM1) is associated with Charcot-Marie-Tooth Type 2P (CMT2P) disease in which loss of LRSAM1 function sensitizes peripheral axons for degeneration. Here, our current study for the first time demonstrates that E3 ubiquitin Ligase LRSAM1 is a really interesting new gene (RING) class protein which suppresses the accumulation of misfolded protein aggregates and also alleviates their deleterious cytotoxic effects. We have also observed that LRSAM1 expression is elevated under neurodegenerative stress conditions, and partial depletion of LRSAM1 endogenous levels aggravates mitochondrial abnormalities and severely affects cell survival during proteotoxic insults. Overall, our current finding indicates that LRSAM1 can alleviate cytotoxic insults mediated by a variety of neurodegeneration linked proteotoxic stress events, and most likely LRSAM1 interplay a significant role in between different components of cellular protein quality control mechanism. This study will also allow us to better comprehend the problem of proteinopathies linked with aberrant protein accumulation and open new possibilities to better elucidate the molecular mechanisms involved in the pathologies of neurodegeneration and aging.

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BACKGROUND: Hepatocellular carcinoma (HCC), the most common primary cancer of the liver, is one of the most common malignancies and the leading cause of cancer-related death worldwide. Leucine-rich repeat and sterile alpha motif containing 1 (LRSAM1) is an E3 ubiquitin ligase involved in diverse cellular activities, including the regulation of cargo sorting, cell adhesion and antibacterial autophagy. The role of LRSAM1 in HCC remains unknown. METHODS: In this study, we reviewed the TCGA database and then performed gain-of-function and loss-of-function analyses of LRSAM1 in HCC cell lines. RESULTS: We found that the mRNA expression level of LRSAM1 was significantly increased in clinical HCC tissues in the TCGA database. Transient LRSAM1 knockdown in several human HCC cell lines led to reduced growth in conventional culture conditions. Stable LRSAM1 knockdown in HepG2 cells led to impaired anchorage-independent growth whereas its stable ectopic overexpression yielded the opposite effects. LRSAM1 overexpression in HepG2 cells enhanced in vivo tumorigenicity, whereas LRSAM1 knockdown in this cell line significantly impaired tumor growth. CONCLUSIONS: Our data suggest that LRSAM1 promotes the oncogenic growth of human HCC cells, although the underlying mechanisms remain to be explored.

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BACKGROUND: Hirschsprung's disease (HSCR) is characterized by missing of enteric neurons in the terminal areas of the whole gut, which is causally related to poor proliferation of enteric neural crest cells (ENCCs). Our aim is to explore how miR-431-5p interacts with its target gene in regulation of proliferation of ENCCs in HSCR. METHODS: Mouse model of HSCR was established by Benzalkonium chloride (BAC) treatment. Quantitative Real-time PCR and western blotting were performed to determine the miR-431-5p and the LRSAM1 expression in colon tissues of the HSCR group (n = 8) and the control group (n = 8) and in ENCCs isolated from colon tissues. CCK-8 assay was performed to detect the proliferation of ENCCs of HSCR. ENCCs after transfection with miR-431-5p mimics or miR-431-5p inhibitor. Luciferase reporter assay was conducted to clarify the connections between miR-431-5p and LRSAM1. RESULTS: Upregulation of miR-431-5p and downregulation of LRSAM1 were found in ENCCs of HSCR. Downregulation of miR-431-5p could promote cell proliferation of ENCCs. LRSAM1 was proved to be the target gene of miR-431-5p by luciferase reporter assay. Moreover, proliferation of ENCCs was increased in the miR-431-5p inhibitor group and was suppressed after knocking down LRSAM1. CONCLUSION: Downregulation of miR-431-5p promoted proliferation of ENCCs via targeting LRSAM1, which provides an innovative and candidate target for treatment of HSCR.

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Cellular protein quality control (PQC) plays a significant role in the maintenance of cellular homeostasis. Failure of PQC mechanism may lead to various neurodegenerative diseases due to accumulation of aberrant proteins. To avoid such fatal neuronal conditions PQC employs autophagy and ubiquitin proteasome system (UPS) to degrade misfolded proteins. Few quality control (QC) E3 ubiquitin ligases interplay an important role to specifically recognize misfolded proteins for their intracellular degradation. Leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1) is a really interesting new gene (RING) class protein that possesses E3 ubiquitin ligase activity with promising applications in PQC. LRSAM1 is also known as RING finger leucine repeat rich (RIFLE) or TSG 101-associated ligase (TAL). LRSAM1 has various cellular functions as it modulates the protein aggregation, endosomal sorting machinery and virus egress from the cells. Thus, this makes LRSAM1 interesting to study not only in protein conformational disorders such as neurodegeneration but also in immunological and other cancerous disorders. Furthermore, LRSAM1 interacts with both cellular protein degradation machineries and hence it can participate in maintenance of overall cellular proteostasis. Still, more research work on the quality control molecular functions of LRSAM1 is needed to comprehend its roles in various protein aggregatory diseases. Earlier findings suggest that in a mouse model of Charcot-Marie-Tooth (CMT) disease, lack of LRSAM1 functions sensitizes peripheral axons to degeneration. It has been observed that in CMT the patients retain dominant and recessive mutations of LRSAM1 gene, which encodes most likely a defective protein. However, still the comprehensive molecular pathomechanism of LRSAM1 in neuronal functions and neurodegenerative diseases is not known. The current article systematically represents the molecular functions, nature and detailed characterization of LRSAM1 E3 ubiquitin ligase. Here, we review emerging molecular mechanisms of LRSAM1 linked with neurobiological functions, with a clear focus on the mechanism of neurodegeneration and also on other diseases. Better understanding of LRSAM1 neurobiological and intracellular functions may contribute to develop promising novel therapeutic approaches, which can also propose new lines of molecular beneficial targets for various neurodegenerative diseases.

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Pectolinarigenin (PEC), a natural flavonoid that is present in citrus fruits, has been reported to exhibit antitumor effects in several cancers. Though the mechanism of PEC-induced cytotoxicity effects has been documented, the proteomic changes that are associated with the cellular response to this flavonoid are poorly understood in gastric cancer cells. In this study, a comparative proteomic analysis was performed to identify proteins associated with PEC-induced cell death in two human gastric cancer cell lines: AGS and MKN-28. Two-dimensional gel electrophoresis (2-DE) revealed a total of 29 and 56 protein spots with significant alteration were screened in AGS and MKN-28 cells respectively. In total, 13 (AGS) and 39 (MKN28) proteins were successfully identified by mass spectrometry from the differential spots and they are known to be involved in signal transduction, apoptosis, transcription and translation, cell structural organization, and metabolism, as is consistent with multiple effects of PEC on tumor cells. Notably, novel target proteins like Probable ATP-dependent RNA helicase DDX4 (DDX4) and E3 ubiquitin-protein ligase LRSAM1 (LRSAM1) along with the commonly differential expressed proteins on both the cell lines that are treated with PEC were confirmed by immunoblotting. The DDX4 accelerates cell cycle progression by abrogating the G2 checkpoint when overexpressed in cancer cells, while the aberrant expression of LRSAM1 may be involved in the cancer pathology. Thus, proteomic analysis provides vital information about target proteins that are important for PEC-induced cell death in gastric cancer cells.

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OBJECTIVE: Deleterious variants in LRSAM1, a RING finger ubiquitin ligase which is also known as TSG101-associated ligase (TAL), have recently been associated with Charcot-Marie-Tooth disease type 2P (CMT2P). The mechanism by which mutant LRSAM1 contributes to the development of neuropathy is currently unclear. The aim of this study was to induce LRSAM1 deficiency in a neuronal cell model, observe its effect on cell growth and morphology and attempt to rescue the phenotype with ancestral and mutant LRSAM1 transfections. MATERIALS AND METHODS: In this experimental study, we investigated the effect of LRSAM1 downregulation on neuroblastoma SH-SY5Y cells by siRNA technology where cells were transfected with siRNA against LRSAM1. The effects on the expression levels of TSG101, the only currently known LRSAM1 interacting molecule, were also examined. An equal dosage of ancestral or mutant LRSAM1 construct was transfected in LRSAM1-downregulated cells to investigate its effect on the phenotype of the cells and whether cell proliferation and morphology could be rescued. RESULTS: A significant reduction in TSG101 levels was observed with the downregulation of LRSAM1. In addition, LRSAM1 knockdown significantly decreased the growth rate of SH-SY5Y cells which is caused by a decrease in cell proliferation. An effect on cell morphology was also observed. Furthermore, we overexpressed the ancestral and the c.2047-1G>A mutant LRSAM1 in knocked down cells. Ancestral LRSAM1 recovered cell proliferation and partly the morphology, however, the c.2047-1G>A mutant did not recover cell proliferation and further aggravated the observed changes in cell morphology. CONCLUSION: Our findings suggest that depletion of LRSAM1 affects neuroblastoma cells growth and morphology and that overexpression of the c.2047-1G>A mutant form, unlike the ancestral LRSAM1, fails to rescue the phenotype.

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Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021-2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.

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LRSAM1, a RING-type E3 ubiquitin ligase, is essential for regulating cargo sorting, signaling pathways, cell adhesion and anti-bacterial autophagy. It is important to elucidate the mechanism that underlies the regulation of LRSAM1 E3 ligase activity. Here, we reported that LRSAM1 exhibited self-association in vitro and in vivo. We found the self-association of LRSAM1 promotes intermolecular ubiquitination and proved a potential N-terminal ubiquitination. The E3 activity of LRSAM1 is amplified when the RING domain is present in tandem with its N-terminal domain(s). Furthermore, we found that the CC2-SAM domain had a strong inhibitory effect on the E3 activity of LRSAM1 in vitro and blocked ubiquitination of TSG101 in vivo; the tandem CC1 domain, but not the individual CC1 domain, could counteract this inhibition. Collectively, our data characterized the self-association of LRSAM1 and showed how its domains may contribute to its overall activity.

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LRSAM1 is a typical RING-finger E3 ubiquitin ligase that plays an important role in many processes. The expression and purification of LRSAM1 from Escherichiacoli had not yet been reported. Here, strategies to clone, express and purify recombinant LRSAM1 in E. coli cells were developed. LRSAM1 was expressed with high yield as inclusion bodies and successfully recovered in soluble form by subsequent denaturation and renaturation steps. Refolded LRSAM1 was directly purified through two steps of ammonium sulfate precipitation, resulting in a purity of up to 95% and a yield of about 6 mg/L bacterial culture. Purified recombinant LRSAM1 exhibited a pH-dependent E3 ligase activity. Its ligase activity was RING-finger domain-dependent, and its ubiquitination favors K6-, K27-, K29- and K48-linkages in cooperation with UbcH5-type E2 enzymes.

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Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions.

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Autophagy is a multistep process that involves the degradation and digestion of intracellular components by the lysosome. It has been proved that many core autophagy-related molecules participate in this event. However, new component proteins that regulate autophagy are still being discovered. At present, we report PHF23 (PHD finger protein 23) with a PHD-like zinc finger domain that can negatively regulate autophagy. Data from experiments indicated that the overexpression of PHF23 impaired autophagy, as characterized by decreased levels of LC3B-II and weakened degradation of endogenous and exogenous autophagic substrates. Conversely, knockdown of PHF23 resulted in opposite effects. Molecular mechanism studies suggested that PHF23 interacts with LRSAM1, which is an E3 ligase key for ubiquitin-dependent autophagy against invading bacteria. PHF23 promotes the ubiquitination and proteasome degradation of LRSAM1. We also show that the PHD finger of PHF23 is a functional domain needed for the interaction with LRSAM1. Altogether, our results indicate that PHF23 is a negative regulator associated in autophagy via the LRSAM1 signaling pathway. The physical and functional connection between the PHF23 and LRSAM1 needs further investigation.

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