Checking folding inside and out

In This Issue In This Issue he ER is a site of both synthesis and quality control. Rejected, improperly folded proteins are destroyed by a well-characterized machinery (the ER-associated degradation [ERAD] pathway) in the cytosol and ER membrane that extracts and chews up any unfolded proteins. But the mechanisms for recognizing unfolded proteins as targets for destruction are less well characterized. The few unfolded substrates to be examined fall into a simple pattern: transmembrane proteins are recognized by one system and soluble, secreted proteins by another. Vashist and Ng (page 41) take a closer look and find that the two transmembrane proteins previously examined had defects in their cytoplasmic domains. When the defects are instead in the lumenal domains of transmem-brane proteins, these proteins are treated in the same way as soluble lumenal proteins. Thus, the two recognition categories depend not on membrane association but on the site of the unfolded domain. Any protein with an unfolded cytoplasmic domain is recognized by one system (ERAD-C), whereas proteins (both transmembrane and soluble) that have unfolded domains in the ER lumen are recognized by a second system (ERAD-L). Proteins subject to ERAD-C are retained in the ER and destroyed rapidly, whereas T Don't digest the messenger elping to create the lysosome is a dangerous job—stick with your task for too long and you might end up as dinner. Seaman (page 111) and Arighi et al. (page 123) now describe how the cation-independent mannose 6-phosphate receptor (CI-MPR) escorts lysosomal enzymes toward their future home but then escapes just in time thanks to a complex of proteins called the retromer. The retromer was first characterized in yeast, where it drags Vps10p from endosomes back to the Golgi. Vps10p and the mammalian CI-MPR have no sequence homology but do perform similar functions. So the researchers tested whether the retromer could also rescue CI-MPR. They first confirmed that both CI-MPR and the mammalian retromer are located in endosomes, with additional CI-MPR in the trans-Golgi network. After either knockout or siRNA knockdown of the retromer component Vps26, far more of the CI-MPR was found in endosomal compartments, with the rest of it spilling over either to the plasma membrane or to a nasty end at the hands of the lysosome. H Without retromer, CI-MPR (red) leaks through to late endosomes and lysosomes (green). This destruction of the CI-MPR apparently compromised its normal function. CI-MPR normally leads lysosomal …