The p24-family and COPII subunit SEC24C facilitate the clearance of alpha1-antitrypsin Z from the endoplasmic reticulum to lysosomes

A subpopulation of the alpha-1-antitrypsin misfolding Z mutant (ATZ) is cleared from the endoplasmic reticulum (ER) via an ER-to-lysosome-associated degradation (ERLAD) pathway. Here, we report that the COPII subunit SEC24C and the p24-family of proteins facilitate the clearance of ATZ via ERLAD. In...

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Published in:Molecular biology of the cell 2024-03, Vol.35 (3), p.mbcE23060257-ar45
Main Authors: Roberts, Benjamin S, Mitra, Debashree, Abishek, Sudhanshu, Beher, Richa, Satpute-Krishnan, Prasanna
Format: Article
Language:English
Subjects:
Analysis
Coordination compounds
Endoplasmic reticulum
Identification and classification
Lysosomes
Properties
Proteins
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Summary:A subpopulation of the alpha-1-antitrypsin misfolding Z mutant (ATZ) is cleared from the endoplasmic reticulum (ER) via an ER-to-lysosome-associated degradation (ERLAD) pathway. Here, we report that the COPII subunit SEC24C and the p24-family of proteins facilitate the clearance of ATZ via ERLAD. In addition to the previously reported ERLAD components calnexin and FAM134B, we discovered that ATZ co-immunoprecipitates with the p24-family members TMP21 and TMED9. This contrasts with wild type alpha1-antitrypsin, which did not co-immunoprecipitate with FAM134B, calnexin or the p24-family members. Live-cell imaging revealed that ATZ and the p24-family members traffic together from the ER to lysosomes. Using chemical inhibitors to block ER exit or autophagy, we demonstrated that p24-family members and ATZ co-accumulate at SEC24C marked ER-exit sites or in ER-derived compartments, respectively. Furthermore, depletion of SEC24C, TMP21 or TMED9 inhibited lysosomal trafficking of ATZ and resulted in the increase of intracellular ATZ levels. Conversely, overexpression of these p24-family members resulted in the reduction of ATZ levels. Intriguingly, the p24-family members co-immunoprecipitate with ATZ, FAM134B and SEC24C. Thus, we propose a model in which the p24-family functions in an adaptor complex linking SEC24C with the ERLAD machinery for the clearance of ATZ. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E23-06-0257