Function of the P97-Ufd1-Npl4 Complex in Retrotranslocation from the ER to the Cytosol: Dual Recognition of Nonubiquitinated Polypeptide Segments and Polyubiquitin Chains

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2003 Jul 9

PMID 12847084

Citations 285

Authors

Yihong Ye

Hemmo H Meyer

Tom A Rapoport

Affiliations

Soon will be listed here.

Abstract

A member of the family of ATPases associated with diverse cellular activities, called p97 in mammals and Cdc48 in yeast, associates with the cofactor Ufd1-Npl4 to move polyubiquitinated polypeptides from the endoplasmic reticulum (ER) membrane into the cytosol for their subsequent degradation by the proteasome. Here, we have studied the mechanism by which the p97-Ufd1-Npl4 complex functions in this retrotranslocation pathway. Substrate binding occurs when the first ATPase domain of p97 (D1 domain) is in its nucleotide-bound state, an interaction that also requires an association of p97 with the membrane through its NH2-terminal domain. The two ATPase domains (D1 and D2) of p97 appear to alternate in ATP hydrolysis, which is essential for the movement of polypeptides from the ER membrane into the cytosol. The ATPase itself can interact with nonmodified polypeptide substrates as they emerge from the ER membrane. Polyubiquitin chains linked by lysine 48 are recognized in a synergistic manner by both p97 and an evolutionarily conserved ubiquitin-binding site at the NH2 terminus of Ufd1. We propose a dual recognition model in which the ATPase complex binds both a nonmodified segment of the substrate and the attached polyubiquitin chain; polyubiquitin binding may activate the ATPase p97 to pull the polypeptide substrate out of the membrane.

Citing Articles

Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity.

Cui Y, Wei J, Fan H, Li W, Zhao L, Wilkinson E Proc Natl Acad Sci U S A. 2024; 121(51):e2407910121.

PMID: 39661064 PMC: 11665913. DOI: 10.1073/pnas.2407910121.

Exploring Endocannabinoid System: Unveiling New Roles in Modulating ER Stress.

Capolupo I, Miranda M, Musella S, Di Sarno V, Manfra M, Ostacolo C Antioxidants (Basel). 2024; 13(11).

PMID: 39594426 PMC: 11591047. DOI: 10.3390/antiox13111284.

Recruitment of Cdc48 to chloroplasts by a UBX-domain protein in chloroplast-associated protein degradation.

Li N, Jarvis R Nat Plants. 2024; 10(9):1400-1417.

PMID: 39160348 PMC: 11410653. DOI: 10.1038/s41477-024-01769-x.

P-NADs: UX-based nobody degraders for ubiquitin-independent degradation of target proteins.

Wang J, Chistov G, Zhang J, Huntington B, Salem I, Sandholu A Heliyon. 2024; 10(14):e34487.

PMID: 39130484 PMC: 11315185. DOI: 10.1016/j.heliyon.2024.e34487.

Valosin-Containing Protein (VCP)/p97 Oligomerization.

Yu G, Bai Y, Zhang Z Subcell Biochem. 2024; 104:485-501.

PMID: 38963497 DOI: 10.1007/978-3-031-58843-3_18.

References

Brodsky J, McCracken A . ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol. 1999; 10(5):507-13. DOI: 10.1006/scdb.1999.0321. View

Shamu C, Story C, Rapoport T, Ploegh H . The pathway of US11-dependent degradation of MHC class I heavy chains involves a ubiquitin-conjugated intermediate. J Cell Biol. 1999; 147(1):45-58. PMC: 2164983. DOI: 10.1083/jcb.147.1.45. View

Hoskins J, Singh S, Maurizi M, Wickner S . Protein binding and unfolding by the chaperone ClpA and degradation by the protease ClpAP. Proc Natl Acad Sci U S A. 2000; 97(16):8892-7. PMC: 16792. DOI: 10.1073/pnas.97.16.8892. View

Zhang X, Shaw A, Bates P, NEWMAN R, Gowen B, Orlova E . Structure of the AAA ATPase p97. Mol Cell. 2001; 6(6):1473-84. DOI: 10.1016/s1097-2765(00)00143-x. View

Hitchcock A, Krebber H, Frietze S, Lin A, Latterich M, Silver P . The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol Biol Cell. 2001; 12(10):3226-41. PMC: 60169. DOI: 10.1091/mbc.12.10.3226. View

Rouiller I, Butel V, Latterich M, Milligan R . A major conformational change in p97 AAA ATPase upon ATP binding. Mol Cell. 2001; 6(6):1485-90. DOI: 10.1016/s1097-2765(00)00144-1. View

Tiwari S, Weissman A . Endoplasmic reticulum (ER)-associated degradation of T cell receptor subunits. Involvement of ER-associated ubiquitin-conjugating enzymes (E2s). J Biol Chem. 2001; 276(19):16193-200. DOI: 10.1074/jbc.M007640200. View

Ellgaard L, Helenius A . ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol. 2001; 13(4):431-7. DOI: 10.1016/s0955-0674(00)00233-7. View

Ogura T, Wilkinson A . AAA+ superfamily ATPases: common structure--diverse function. Genes Cells. 2001; 6(7):575-97. DOI: 10.1046/j.1365-2443.2001.00447.x. View

10.

Dai R, Li C . Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol. 2001; 3(8):740-4. DOI: 10.1038/35087056. View

11.

Shamu C, Flierman D, Ploegh H, Rapoport T, Chau V . Polyubiquitination is required for US11-dependent movement of MHC class I heavy chain from endoplasmic reticulum into cytosol. Mol Biol Cell. 2001; 12(8):2546-55. PMC: 58612. DOI: 10.1091/mbc.12.8.2546. View

12.

Coles M, Diercks T, Liermann J, Groger A, Rockel B, Baumeister W . The solution structure of VAT-N reveals a 'missing link' in the evolution of complex enzymes from a simple betaalphabetabeta element. Curr Biol. 1999; 9(20):1158-68. DOI: 10.1016/S0960-9822(00)80017-2. View

13.

Golbik R, Lupas A, Koretke K, Baumeister W, Peters J . The Janus face of the archaeal Cdc48/p97 homologue VAT: protein folding versus unfolding. Biol Chem. 1999; 380(9):1049-62. DOI: 10.1515/BC.1999.131. View

14.

Rape M, Hoppe T, Gorr I, Kalocay M, Richly H, Jentsch S . Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell. 2001; 107(5):667-77. DOI: 10.1016/s0092-8674(01)00595-5. View

15.

Fang S, Ferrone M, Yang C, Jensen J, Tiwari S, Weissman A . The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001; 98(25):14422-7. PMC: 64697. DOI: 10.1073/pnas.251401598. View

16.

Bays N, Wilhovsky S, Goradia A, Hampton R . HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell. 2001; 12(12):4114-28. PMC: 60780. DOI: 10.1091/mbc.12.12.4114. View

17.

Ye Y, Meyer H, Rapoport T . The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001; 414(6864):652-6. DOI: 10.1038/414652a. View

18.

Rabinovich E, Kerem A, Frohlich K, Diamant N, Bar-Nun S . AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol. 2002; 22(2):626-34. PMC: 139744. DOI: 10.1128/MCB.22.2.626-634.2002. View

19.

Hetzer M, Meyer H, Walther T, Warren G, Mattaj I . Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nat Cell Biol. 2002; 3(12):1086-91. DOI: 10.1038/ncb1201-1086. View

20.

Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf D . Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol. 2002; 4(2):134-9. DOI: 10.1038/ncb746. View