Sorting nexin 10 (SNX10) facilitates the trafficking of cathepsin A (CTSA) into lysosomes where it is processed into its active form. For example, a redox-sensitive transcription factor, namely nuclear factor erythroid 2-related factor 2 (NRF2), controls the basal and inducible expression of LAMP2A and CMA activity. Several transcription factors are reported to regulate LAMP2A expression. LAMP2A being the rate-limiting factor of CMA, its expression and/or stabilization of the protein is crucial to that process. LAMP2A knockout results in a decreased CMA activity, which leads to increased PLIN2 expression, decreased lipid oxidation and subsequent LD accumulation. The selective degradation of cytosolic proteins by CMA depends, at least in part, on the availability of LAMP2A receptor at the lysosomal membrane. Chaperone heat shock cognate 71 kDa protein (HSC70) recognizes and binds to the KFERQ-like motif of PLIN2 and transports it to the LAMP2A for degradation. PLIN2 is one of the representative CMA substrate proteins associated with lipid metabolism. In a CMA-deficient model system, the degradation of the coat proteins was inhibited and the association of autophagy proteins and lysosome-associated membrane glycoprotein 1 (LAMP1) with LDs was decreased, resulting in LD accumulation and steatosis. Therefore, PLINs are believed to play a role as gatekeepers in LD mobilization. A recent study demonstrated that selective removal of the LD surface proteins, PLIN2 and PLIN3, by chaperone-medicated autophagy (CMA) is the initial step facilitating the degradation of the lipid component of the LD core by lipolysis or lipophagy. Degradation of LDs occurs either through enzymatic lipolysis or autophagy: lipolysis is characterized by phosphorylation and proteasomal degradation of PLIN1 and subsequent activation of adipose triglyceride lipase in autophagy, a small portion of LDs are selectively sequestered in autophagosomes and delivered to lysosomes for degradation. Synthesis and degradation of LDs are controlled by diverse cellular signaling in response to the energy and metabolic balance. LDs consist of a neutral lipid core encircled by a phospholipid monolayer and a family of coat proteins such as perilipins (PLINs). Lipid droplets (LDs) are dynamic cytoplasmic organelles serving an essential function as lipid reservoirs and providing substrates for energy metabolism. Keywords: Chaperone-mediated autophagy, Diclofenac, NSAIDs, Perilipin 2, Sorting nexin 10 Introduction In turn, impaired CMA failed to degrade PLIN2 and disrupted cellular lipid homeostasis, thus leading to NSAID-induced steatosis and hepatotoxicity. Upregulation of sorting nexin 10 (SNX10) via the CHOP-dependent endoplasmic reticulum stress response and thus maturation of cathepsin A (CTSA) was shown to be responsible for the lysosomal degradation of LAMP2A by diclofenac.Ĭonclusion: We demonstrated that NSAIDs induced SNX10- and CTSA-dependent degradation of LAMP2A, thereby leading to the suppression of CMA. Reactivation of CMA by treatment with AR7 or overexpression of LAMP2A inhibited diclofenac-induced lipid accumulation and hepatotoxicity. NSAIDs inhibited CMA, as reflected by the decreased expression of lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A) protein, the increased expression of CMA substrate proteins such as PLIN2, and the decreased activity of photoactivatable KFERQ-PAmCherry reporter. Diclofenac-induced lipid accumulation was confirmed in both mouse primary hepatocytes and the liver of mice. Results: All tested NSAIDs in this study accumulated neutral lipids in hepatocytes, diclofenac having demonstrated the most potency in that regard. The effect of NSAID on CMA inhibition was evaluated in vivo using diclofenac and CMA activator (AR7) administered mice. The activity of chaperone-mediated autophagy (CMA) was determined by western blotting, qRT-PCR, and confocal imaging. Lipid accumulation was measured using Nile-red assay and BODIPY 493/503. Methods: Mouse primary hepatocytes and HepG2 cells were used to examine the underlying mechanism of NSAID-induced hepatic steatosis. This study presented the mechanism by which NSAIDs induce hepatic lipid accumulation. Rationale: While some non-steroidal anti-inflammatory drugs (NSAIDs) are reported to induce hepatic steatosis, the molecular mechanisms are poorly understood. Select the file that you have just downloaded and select import option Reference Manager (RIS). SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Lee W, Kim HY, Choi YJ, Jung SH, Nam YA, Zhang Y, Yun SH, Chang TS, Lee BH.
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