Jiayu Lin, Xinyue Wei, Yan Dai, Haorui Lu, Yajian Song, Jiansong Ju, Rihan Wu, Qichen Cao, Hao Yang, Lang Rao
{"title":"Chaperone-mediated autophagy degrades SERPINA1<sup>E342K</sup>/α1-antitrypsin Z variant and alleviates cell stress.","authors":"Jiayu Lin, Xinyue Wei, Yan Dai, Haorui Lu, Yajian Song, Jiansong Ju, Rihan Wu, Qichen Cao, Hao Yang, Lang Rao","doi":"10.1080/15548627.2025.2480037","DOIUrl":null,"url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1<sup>E342K</sup>/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1<sup>E342K</sup>/ATZ accumulation; suppressing CMA worsens SERPINA1<sup>E342K</sup>/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1<sup>E342K</sup>/ATZ breakdown. Specifically, SERPINA1<sup>E342K</sup>/ATZ's <sub>121</sub>QELLR<sub>125</sub> motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1<sup>E342K</sup>/ATZ. This selective activation of CMA operates independently of other autophagy pathways and alleviates SERPINA1<sup>E342K</sup>/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1<sup>E342K</sup>/ATZ elimination and mitigates hepatic SERPINA1<sup>E342K</sup>/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1<sup>E342K</sup>/ATZ and place it as a novel target for AATD treatment.<b>Abbreviation:</b> AR7: atypical retinoid 7; ATG16L1: autophagy related 16 like 1; AATD: SERPINA1/alpha-1 antitrypsin deficiency; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; PAS-D: periodic acid-Schiff plus diastase; SERPINA1/A1AT: serpin family A member 1; SERPINA1<sup>E342K</sup>/ATZ: Z variant of SERPINA1; TMRE: tetramethyl rhodamine ethyl ester perchlorate.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Autophagy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/15548627.2025.2480037","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress.
Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1E342K/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1E342K/ATZ accumulation; suppressing CMA worsens SERPINA1E342K/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1E342K/ATZ breakdown. Specifically, SERPINA1E342K/ATZ's 121QELLR125 motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1E342K/ATZ. This selective activation of CMA operates independently of other autophagy pathways and alleviates SERPINA1E342K/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1E342K/ATZ elimination and mitigates hepatic SERPINA1E342K/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1E342K/ATZ and place it as a novel target for AATD treatment.Abbreviation: AR7: atypical retinoid 7; ATG16L1: autophagy related 16 like 1; AATD: SERPINA1/alpha-1 antitrypsin deficiency; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; PAS-D: periodic acid-Schiff plus diastase; SERPINA1/A1AT: serpin family A member 1; SERPINA1E342K/ATZ: Z variant of SERPINA1; TMRE: tetramethyl rhodamine ethyl ester perchlorate.
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