V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation

Yiwei Sun; Xi'e Wang; Xiaotong Yang; Lei Wang; Jingjin Ding; Chih-Chen Wang; Hong Zhang; Xi Wang

doi:10.1016/j.devcel.2023.10.007

V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation

Dev Cell. 2023 Dec 4;58(23):2761-2775.e5. doi: 10.1016/j.devcel.2023.10.007. Epub 2023 Nov 2.

Authors

Yiwei Sun¹, Xi'e Wang², Xiaotong Yang¹, Lei Wang¹, Jingjin Ding², Chih-Chen Wang¹, Hong Zhang¹, Xi Wang³

Affiliations

¹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: wangxi@ibp.ac.cn.

PMID: 37922908
DOI: 10.1016/j.devcel.2023.10.007

Abstract

Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we discover that Z-AAT, a disease-causing mutant of α1-antitrypsin, induces noncanonical ER-phagy at ER exit sites (ERESs). Accumulation of misfolded Z-AAT at the ERESs impairs coat protein complex II (COPII)-mediated ER-to-Golgi transport and retains V0 subunits that further assemble V-ATPase at the arrested ERESs. V-ATPase subsequently recruits ATG16L1 onto ERESs to mediate in situ lipidation of LC3C. FAM134B-II is then recruited by LC3C via its LIR motif and elicits ER-phagy leading to efficient lysosomal degradation of Z-AAT. Activation of this ER-phagy mediated by the V-ATPase-ATG16L1-LC3C axis (EVAC) is also triggered by blocking ER export. Our findings identify a pathway which switches COPII-mediated transport to lysosomal degradation for ER quality control.

Keywords: ATG16L1; COPII; ER exit sites; ER-phagy; LC3C; Sec24C; V-ATPase; autophagy; protein quality control; α1 antitrypsin.

MeSH terms

Adenosine Triphosphatases* / metabolism
Autophagy
Endoplasmic Reticulum / metabolism
Golgi Apparatus / metabolism
Lysosomes* / metabolism
Protein Transport / physiology

Substances

Adenosine Triphosphatases