presented his group's efforts to understand how organelle shapes are formed and maintained. The fi ndings identify two protein families that create tubules out of ER membrane. A sphere is the most stable membrane shape; deformations that increase membrane curvature cost energy and must be actively stabilized. Rapoport and colleagues, including Gia Voeltz, used an in vitro system for ER network formation to identify factors that create curved membrane shapes. With just membranes, salt, and GTP, their system produces a network of ER tubules.< I D > J C B 1 7 2 4 M R _ F i g. 1. e p s < / I D > This simple, self-contained system was not ideal for identifying the shape-creating components. "When we fi rst saw [that] everything was already in the membrane," said Rapoport in his talk, "we thought, 'what a bummer.'" But the group found a way around this diffi culty by using small molecule inhibitors to block in vitro ER formation, and then identifying the inhibitors' targets. One such target was an integral membrane protein called Reticulon4a (Rtn4a), previously named for its localization to ER membranes. All eukaryotes express at least one homologue of Rtn4a, and the proteins are the fi rst known markers specifi cally localized to the tubular ER and absent from sheets. Cells overexpressing Rtn proteins formed more tubules, but loss of the two yeast members did not prevent tubule formation under normal conditions. Only when mutant cells were subjected to osmotic stress were their tubules lost. Rtn proteins form homo-and hetero-oligomers, so the group fi gured that another Rtn-interacting protein might be required for tubule formation. Indeed, they found that Rtn pulled down another ubiquitous integral membrane protein called DP-1. Loss of both the yeast DP-1 and the more abundant of its two Rtns now blocked tubule formation. The group has proposed that Rtn and DP-1 might be wedge-shaped, with their wider sides in the outer membrane leafl et. The presence of these proteins would thus favor a highly curved membrane. They now plan to test whether purifi ed Rtn and DP-1 can turn liposomes into tubules. NL

In eukaryotic cells, incorrectly folded proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded by the proteasome. This pathway is co-opted by some viruses. For example, the US11 protein of the human cytomegalovirus targets the major histocompatibility complex class I heavy chain for cytosolic degradation. How proteins are extracted from the ER membrane is unknown. In bacteria and mitochondria, members of the AAA ATPase family are involved in extracting and degrading membrane proteins. Here we demonstrate that another member of this family, Cdc48 in yeast and p97 in mammals, is required for the export of ER proteins into the cytosol. Whereas Cdc48/p97 was previously known to function in a complex with the cofactor p47 (ref. 5) in membrane fusion, we demonstrate that its 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.

The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus gene US2 specifies a product capable of dislocating MHC class I molecules from the endoplasmic reticulum to the cytosol and delivering them to the proteasome. This process involves the Sec61 complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.