Journal
JOURNAL OF CELL BIOLOGY
Volume 188, Issue 2, Pages 223-235Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200910042
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Funding
- The Foundation for Research on Neurodegenerative Diseases
- Onelife Advisors SA
- The Swiss National Center of Competence in Research on Neural Plasticity and Repair
- Swiss National Science Foundation
- The Synapsis Foundation
- The BangerterRhyner Foundation
- Grants-in-Aid for Scientific Research [20249052, 23659176] Funding Source: KAKEN
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Sophisticated quality control mechanisms prolong retention of protein-folding intermediates in the endoplasmic reticulum (ER) until maturation while sorting out terminally misfolded polypeptides for ER-associated degradation (ERAD). The presence of structural lesions in the luminal, transmembrane, or cytosolic domains determines the classification of misfolded polypeptides as ERAD-L, -M, or -C substrates and results in selection of distinct degradation pathways. In this study, we show that disposal of soluble (nontransmembrane) polypeptides with luminal lesions (ERAD-L-S substrates) is strictly dependent on the E3 ubiquitin ligase HRD1, the associated cargo receptor SEL1L, and two interchangeable ERAD lectins, OS-9 and XTP3-B. These ERAD factors become dispensable for degradation of the same polypeptides when membrane tethered (ERAD-L-M substrates). Our data reveal that, in contrast to budding yeast, tethering of mammalian ERAD-L substrates to the membrane changes selection of the degradation pathway.
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