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
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 recruitsATG16L1onto 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.
附件下载：
V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation, Dev Cell, 2 Nov 2023
Developmental Cell, 2 November, 2023, DOI：https://doi.org/10.1016/j.devcel.2023.10.007
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
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 recruitsATG16L1onto 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.
文章链接：https://www.sciencedirect.com/science/article/pii/S1534580723005269?via%3Dihub