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ER ‐to‐lysosome‐associated degradation of proteasome‐resistant ATZ polymers occurs via receptor‐mediated vesicular transport
Author(s) -
Fregno Ilaria,
Fasana Elisa,
Bergmann Timothy J,
Raimondi Andrea,
Loi Marisa,
Soldà Tatiana,
Galli Carmela,
D'Antuono Rocco,
Morone Diego,
Danieli Alberto,
Paganetti Paolo,
Anken Eelco,
Molinari Maurizio
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899259
Subject(s) - biology , lysosome , degradation (telecommunications) , microbiology and biotechnology , proteasome , receptor , ubiquitin , biochemistry , enzyme , gene , telecommunications , computer science
Maintenance of cellular proteostasis relies on efficient clearance of defective gene products. For misfolded secretory proteins, this involves dislocation from the endoplasmic reticulum ( ER ) into the cytosol followed by proteasomal degradation. However, polypeptide aggregation prevents cytosolic dislocation and instead activates ill‐defined lysosomal catabolic pathways. Here, we describe an ER ‐to‐lysosome‐associated degradation pathway ( ERLAD ) for proteasome‐resistant polymers of alpha1‐antitrypsin Z ( ATZ ). ERLAD involves the ER ‐chaperone calnexin (CNX) and the engagement of the LC 3 lipidation machinery by the ER ‐resident ER ‐phagy receptor FAM 134B, echoing the initiation of starvation‐induced, receptor‐mediated ER ‐phagy. However, in striking contrast to ER ‐phagy, ATZ polymer delivery from the ER lumen to LAMP 1/ RAB 7‐positive endolysosomes for clearance does not require ER capture within autophagosomes. Rather, it relies on vesicular transport where single‐membrane, ER ‐derived, ATZ ‐containing vesicles release their luminal content within endolysosomes upon membrane:membrane fusion events mediated by the ER ‐resident SNARE STX 17 and the endolysosomal SNARE VAMP 8. These results may help explain the lack of benefits of pharmacologic macroautophagy enhancement that has been reported for some luminal aggregopathies.