Quality control of protein complex assembly by a transmembrane recognition factor

The inner nuclear membrane (INM) is continuous withthe endoplasmic reticulum (ER) but harbors a distinc-tive proteome essential for nuclear functions. Inyeast, the Asi1/Asi2/Asi3 ubiquitin ligase complexsafeguards the INM proteome through the clearanceof mislocalized ER membrane proteins. How the Asicomplex selectively targets mislocalized proteinsand coordinates its activity with other ER functions,such as protein biogenesis, is unclear. Here, we un-cover a link between INM proteome identity andmembrane protein complex assembly in the remain-ing ER. We show that lone proteins and complex sub-units failing to assemble in the ER access the INM forAsi-mediated degradation. Substrates are recog-nized by direct binding of Asi2 to their transmem-brane domains for subsequent ubiquitination byAsi1/Asi3 and membrane extraction. Our data sug-gest a model in which spatial segregation of mem-brane protein complex assembly and quality controlimproves assembly efficiency and reduces the levelsof orphan subunits