MutLα: At the Cutting Edge of Mismatch Repair

Hrd1p and Doa10p organize factors used for the recognition, ubiquitination, and extraction of substrates. Indeed, Hrd1p provides the direct physical link between recognition events in the ER lumen and ubiquitination and extraction activities in the cytosol (Carvalho et al., 2006; Denic et al., 2006; Gauss et al., 2006). However, many pressing questions remain. Left out of the discussion is a second nonredundant lectin, Htm1p (EDEM in mammals), which is crucial in ERAD-L. Also, how substrates are moved to the cytosol remains elusive. The identity of the dislocation pore in ERAD-L remains controversial and whether such a conduit is even needed in ERAD-C and ERAD-M is unknown. Unlike the Hrd1p complex, there are no clear ideas on how the Doa10p complex participates in selecting substrates. There is no doubt, however, that the crucial framework these new studies provides will accelerate the resolution of these and other mysteries of how molecular inspectors carry out their work in ER quality control.