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 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.
Ye
Y
Y
Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Meyer
H H
HH
Rapoport
T A
TA
D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D043402:Cathepsin A; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006183:H-2 Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins; D017510:Protein Folding; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014407:Tumor Cells, Cultured; D000074405:Valosin Containing Protein; D033921:Vesicular Transport Proteins
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C104361:NPL4 protein, S cerevisiae; C498751:Nsfl1c protein, rat; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; C444652:UFD1 protein, S cerevisiae; C491497:UFD1 protein, human; C491496:Ufd1 protein, rat; D033921:Vesicular Transport Proteins; D002268:Carboxypeptidases; D043402:Cathepsin A; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein