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  • Title: HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains.
    Author: Kamada Y, Ohnishi Y, Nakashima C, Fujii A, Terakawa M, Hamano I, Nakayamada U, Katoh S, Hirata N, Tateishi H, Fukuda R, Takahashi H, Lukacs GL, Okiyoneda T.
    Journal: J Cell Biol; 2024 Jul 01; 223(7):. PubMed ID: 38722278.
    Abstract:
    Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to mediate the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 uniquely promotes CFTR ERAD. In vitro assay revealed that HERC3 directly interacts with the exposed membrane-spanning domains (MSDs) of CFTR but not with the MSDs embedded in liposomes. Therefore, HERC3 could play a role in the quality control of MSDs in the cytoplasm and might be crucial for the ERAD pathway of select membrane proteins.
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