Molecular Info®

Molecular Info® Copy Right © 2001 Institute of Molecular Development LLC

RETRO-TRANSLOCATION OF PROTEINS FROM THE ENDOPLASMIC RETICULUM INTO THE CYTOSOL Billy Tsai, Yihong Ye & Tom A. Rapoport The Nature Reviews Molecular Cell Biology April 2002, 3: 246 -255. Proteins that are misfolded in the endoplasmic reticulum are transported back into the cytosol for destruction by the proteasome. When newly synthesized proteins translocate into the endoplasmic reticulum (ER) lumen, they undergo 'quality control'. An elaborate system of chaperones helps proteins to fold and prevents misfolded polypeptides from reaching their final destination. Misfolded proteins that cannot be brought back to their native state are degraded. Recent evidence indicates that misfolded proteins are retro-translocated from the ER lumen to the cytosol and are then degraded by the ubiquitin proteasome system. The retro-translocation pathway is co-opted by certain viruses to degrade proteins that are involved in the immunoprotection of the host. It is also used by some plant and bacterial toxins to enter the cytosol of cells. The first step in retro-translocation is the recognition of a misfolded substrate. Exposure of hydrophobic polypeptide patches might represent the general recognition signal and ER chaperones might be the signal receptors. An important player seems to be protein disulphide isomerase and its relatives. BiP and other chaperones have also been implicated in targeting misfolded substrates for retro-translocation. The next step in retro-translocation is the transport of the polypeptide chain across the ER membrane. On the basis of biochemical and genetic data, transport of the polypeptide seems to occur through the protein-conducting channel that is formed by the Sec61 complex. Given the size limitation of the Sec61 channel, it is likely that substrates need to be at least partially unfolded before they can pass through the channel. Polypeptide substrates that emerge from the translocation channel are polyubiquitylated at the membrane. The ubiquitylation machinery comprises both specific conjugation and ligase enzymes. However, polyubiquitylation alone is insufficient to release a substrate into the cytosol. Recent experiments indicate a role for a member of the AAA family of ATPases Cdc48 in yeast and p97 in mammals in extracting polypeptides from the ER membrane. These ATPases might 'pull' polypeptides out of the membrane in a similar manner to AAA proteases, which remove misfolded membrane proteins in bacteria and mitochondria.