Chaperone-mediated autophagy is an overlooked pathway for mutant α1-antitrypsin Z degradation

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 HSC70 for substrate recognition. In α1-antitrypsin deficiency (AATD), a disease characterized by the hepatic build-up of α1-Antitrypsin Z mutant (ATZ), CMA’s role had been unclear. This work demonstrates the critical role that CMA plays in preventing ATZ accumulation; suppressing CMA worsens ATZ accumulation, whilst activating it through chemical stimulation or LAMP2A overexpression promotes ATZ breakdown. Specifically, ATZ’s 121QELLR125 motif is critical for HSC70 recognition and LAMP2A’s charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of ATZ. This selective activation of CMA operates independently from other autophagy pathways and alleviate ATZ aggregates caused cellular stress. These findings highlight CMA’s critical function in cellular protein quality control of ATZ and place it as a novel target for AATD treatment approaches.