摘要：SummaryER-associated degradation (ERAD) targets misfolded ER proteins for degradation. Retrotranslocation, a key feature of ERAD, entails removal of ubiquitinated substrates into the cytosol for proteasomal destruction. Recently, it has been shown that the Hrd1 E3 ligase forms a retrotranslocation channel for luminal (ERAD-L) substrates. Conversely, our studies found that integral membrane (ERAD-M) substrates exit the ER through a distinct pathway mediated by the Dfm1 rhomboid protein. Those studies also revealed a second, Hrd1-dependent pathway of ERAD-M retrotranslocation can arise indfm1Δnull. Here we show that, in thedfm1Δnull, the HRD complex undergoes remodeling to a form that mediates ERAD-M retrotranslocation. Specifically, Hrd1's normally present stochiometric partner Hrd3 is efficiently removed during suppressive remodeling, allowing Hrd1 to function in this novel capacity. Neither Hrd1 autoubiquitination nor its cytosolic domain is required for suppressive ERAD-M retrotranslocation. Thus, the HRD complex displays remarkable functional flexibility in response to ER stress.Graphical AbstractDisplay OmittedHighlights•Rhomboid derlin Dfm1 is the major mediator of ERAD-M retrotranslocation•Indfm1Δnulls, there is a growth stress imposed by high levels of ERAD-M substrates•Indfm1Δ, Hrd1 is elevated and Hrd3 is removed to restore ERAD-M retrotranslocation•Hrd1's autoubiquitination activity is dispensable for restored ERAD-M retrotranslocationBiological Sciences; Molecular Biology; Cell Biology
