Chaperone-mediated autophagy degrades SERPINA1 E342K /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 from 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 approaches.