Glycoprotein-specific ubiquitin ligases recognize N-glycans in unfolded substrates

Misfolded or unassembled polypeptides in the endoplasmic reticulum ( ER) are retro-translocated into the cytosol and degraded by the ubiquitin - proteasome system. We reported previously that the SCFFbs1,2 ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway. Here we investigated how the SCFFbs1,2 complexes interact with unfolded glycoproteins. The SCFFbs1 complex was associated with p97/VCP AAA ATPase and bound to integrin-beta1, one of the SCFFbs1 substrates, in the cytosol in a manner dependent on p97 ATPase activity. Both Fbs1 and Fbs2 proteins interacted with denatured glycoproteins, which were modified with not only high-mannose but also complex-type oligosaccharides, more efficiently than native proteins. Given that Fbs proteins interact with innermost chitobiose in N-glycans, we propose that Fbs proteins distinguish native from unfolded glycoproteins by sensing the exposed chitobiose structure.