2. Academic Validation
  3. Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress

Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress

  • Autophagy. 2025 Aug;21(8):1662-1679. doi: 10.1080/15548627.2025.2480037.
Jiayu Lin 1 2,  Xinyue Wei 2 3,  Yan Dai 1 2,  Haorui Lu 2,  Yajian Song 1,  Jiansong Ju 3,  Rihan Wu 4,  Qichen Cao 2 5,  Hao Yang 4,  Lang Rao 2 5
Affiliations

Affiliations

  • 1 College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China.
  • 2 State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
  • 3 College of Life Science, Hebei Normal University, Shijiazhuang, China.
  • 4 Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia Autonomous Region, China.
  • 5 National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
PMID: 40114294 DOI: 10.1080/15548627.2025.2480037
Abstract

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.

Keywords

Cellular stress; HSPA8/HSC70; LAMP2A; chaperone-mediated autophagy; protein degradation.

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