Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that eliminates potentially toxic unfolded proteins from the ER. ERAD involves the transport of substrates from the ER to the cytosol, a process termed retrotranslocation, followed by their polyubiquitylation and proteasomal degradation. However, the molecular details of how ERAD targets are regulated remain poorly understood. Now, by performing a focused siRNA and immunoblot-based screen, Michael Boutros and colleagues (Wolf et al., 2021) identify novel components involved in ERAD-mediated control of EVI (also known as WLS; hereafter EVI/WLS), a transmembrane protein that the authors previously reported to be important for WNT secretion. Investigating the candidates from their screen, they show that ERLIN2 already interacts with EVI/WLS prior to its polyubiquitylation and propose that it connects EVI/WLS to the ubiquitylation machinery. FAF2 and UBXN4, proteins which harbour VCP-binding domains and are thus likely involved in retrotranslocation, interact with polyubiquitylated EVI/WLS, and the E2 ubiquitin-conjugating enzymes UBE2N and UBE2K further modify EVI/WLS with ubiquitin with various linkage types. Finally, the authors also reveal that knockdown of UBE2N increases the secretion of WNT ligands; interestingly however, EVI/WLS ubiquitylation and degradation occurs irrespectively of cellular WNT levels. Collectively, this study sheds light on the mechanism of how an ERAD substrate is ubiquitylated and links the ubiquitin-proteasome system to the WNT pathway.
Dissecting the regulation of an ERAD substrate
Dissecting the regulation of an ERAD substrate. J Cell Sci 15 August 2021; 134 (16): e134_e1602. doi:
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