The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

In eukaryotic cells, incorrectly folded proteins in the endoplasmic reticul um (ER) are exported into the cytosol and degraded by the proteasome(1). Th is pathway is co-opted by some viruses. For example, the US11 protein of th e human cytomegalovirus targets the major histocompatibility complex class I heavy chain for cytosolic degradation(2). How proteins are extracted from the ER membrane is unknown. In bacteria and mitochondria, members of the A AA ATPase family are involved in extracting and degrading membrane proteins (3,4). Here we demonstrate that another member of this family, Cdc48 in yea st and p97 in mammals, is required for the export of ER proteins into the c ytosol. Whereas Cdc48/p97 was previously known to function in a complex wit h the cofactor p47 (ref. 5) in membrane fusion(6-8), we demonstrate that it s role in ER protein export requires the interacting partners Ufd1 and Npl4 . The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.