Gene Symbol: NPL4
Description: Npl4p
Alias: HRD4, Npl4p
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. 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;107:667-77 pubmed
    ..p90 is liberated from its partner for nuclear targeting by the activity of the chaperone-like CDC48(UFD1/NPL4) complex...
  2. 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;12:3226-41 pubmed
    ..We now show that a membrane-associated complex containing the highly conserved Npl4p, Ufd1p, and Cdc48p proteins mediates the proteasome-regulated cleavage of Mga2p and Spt23p...
  3. Bays N, Wilhovsky S, Goradia A, Hodgkiss Harlow K, Hampton R. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell. 2001;12:4114-28 pubmed
    ..We also found that each member of the Cdc48p-Ufd1p-Npl4p complex is individually required for ERAD.
  4. Ye Y, Meyer H, Rapoport T. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001;414:652-6 pubmed
    ..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 ..
  5. Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf D, et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol. 2002;4:134-9 pubmed
    ..Moreover, our results suggest that the AAA proteins of the 26S proteasome are not directly involved in substrate export. Instead, a related AAA complex Cdc48, is required for ER-associated protein degradation upstream of the proteasome. ..
  6. Ye Y, Meyer H, Rapoport T. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol. 2003;162:71-84 pubmed
    ..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 ..
  7. Verma R, Oania R, Fang R, Smith G, Deshaies R. Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol Cell. 2011;41:82-92 pubmed publisher
    ..UV-induced turnover of Rpb1 depends upon Cdc48-Ufd1-Npl4, Ubx4, and the uncharacterized adaptor Ubx5...
  8. Fujii K, Kitabatake M, Sakata T, Ohno M. 40S subunit dissociation and proteasome-dependent RNA degradation in nonfunctional 25S rRNA decay. EMBO J. 2012;31:2579-89 pubmed publisher
    ..Here, using genetic screening, we identified two ubiquitin-binding complexes, the Cdc48-Npl4-Ufd1 complex (Cdc48 complex) and the proteasome, as the factors involved in 25S NRD...
  9. Neuber O, Jarosch E, Volkwein C, Walter J, Sommer T. Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat Cell Biol. 2005;7:993-8 pubmed
    ..Thus, a complex comprising the AAA ATPase, a ubiquitin ligase and the recruitment factor Ubx2 has a central role in ER-associated proteolysis. ..

More Information


  1. Rumpf S, Jentsch S. Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. Mol Cell. 2006;21:261-9 pubmed
    ..We propose that the balance between the distinct substrate-processing cofactors may determine whether a substrate is multiubiquitylated and routed to the proteasome for degradation or deubiquitylated and/or released for other purposes. ..
  2. Barbin L, Eisele F, Santt O, Wolf D. The Cdc48-Ufd1-Npl4 complex is central in ubiquitin-proteasome triggered catabolite degradation of fructose-1,6-bisphosphatase. Biochem Biophys Res Commun. 2010;394:335-41 pubmed publisher
    ..As an additional machinery required for the catabolite degradation process, we identified the trimeric Cdc48(Ufd1-Npl4) complex and the ubiquitin receptors Dsk2 and Rad23...
  3. NEAL S, Mak R, Bennett E, HAMPTON R. A Cdc48 "Retrochaperone" Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates. J Biol Chem. 2017;292:3112-3128 pubmed publisher
    ..All components of the canonical Cdc48 complex Cdc48-Npl4-Ufd1 were present in solubilized ERAD-M substrates...
  4. Heo J, Livnat Levanon N, Taylor E, Jones K, Dephoure N, Ring J, et al. A stress-responsive system for mitochondrial protein degradation. Mol Cell. 2010;40:465-80 pubmed publisher
    ..We demonstrate that Vms1 is a required component of an evolutionarily conserved system for mitochondrial protein degradation, which is necessary to maintain mitochondrial, cellular, and organismal viability. ..
  5. Bosis E, Salomon D, Ohayon O, Sivan G, Bar Nun S, Rabinovich E. Ssz1 restores endoplasmic reticulum-associated protein degradation in cells expressing defective cdc48-ufd1-npl4 complex by upregulating cdc48. Genetics. 2010;184:695-706 pubmed publisher
    ..The key role of Cdc48p-Ufd1p-Npl4p is indicated by impaired ERAD in Saccharomyces cerevisiae with mutations in any of this complex's genes...
  6. Shcherbik N, Haines D. Cdc48p(Npl4p/Ufd1p) binds and segregates membrane-anchored/tethered complexes via a polyubiquitin signal present on the anchors. Mol Cell. 2007;25:385-97 pubmed
    ..performs ubiquitin-selective functions, which are mediated by numerous ubiquitin binding adaptors, including the Npl4p-Ufd1p complex...
  7. Gauss R, Sommer T, Jarosch E. The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 2006;25:1827-35 pubmed
    ..Thus, the Hrd1p ligase complex unites substrate selection in the ER lumen and polyubiquitination in the cytoplasm and links these processes to the release of ER proteins via the Cdc48p complex. ..
  8. Schuberth C, Buchberger A. Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat Cell Biol. 2005;7:999-1006 pubmed
    ..Lack of Ubx2 causes defects in ERAD that are exacerbated under stress conditions. These findings are consistent with a model in which Ubx2 coordinates the assembly of a highly efficient ERAD machinery at the ER membrane. ..
  9. Carvalho P, Goder V, Rapoport T. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006;126:361-73 pubmed
    ..All three pathways converge at the Cdc48p ATPase complex. These results lead to a unifying concept for ERAD that may also apply to mammalian cells. ..
  10. Auld K, Hitchcock A, Doherty H, Frietze S, Huang L, Silver P. The conserved ATPase Get3/Arr4 modulates the activity of membrane-associated proteins in Saccharomyces cerevisiae. Genetics. 2006;174:215-27 pubmed
    The regulation of cellular membrane dynamics is crucial for maintaining proper cell growth and division. The Cdc48-Npl4-Ufd1 complex is required for several regulated membrane-associated processes as part of the ubiquitin-proteasome ..
  11. Stein A, Ruggiano A, Carvalho P, Rapoport T. Key steps in ERAD of luminal ER proteins reconstituted with purified components. Cell. 2014;158:1375-1388 pubmed publisher
    ..Cdc48p-dependent membrane extraction of polyubiquitinated proteins can be reproduced with reconstituted proteoliposomes. Our results suggest a model for retrotranslocation in which Hrd1p forms a membrane conduit for misfolded proteins. ..
  12. Hitchcock A, Auld K, Gygi S, Silver P. A subset of membrane-associated proteins is ubiquitinated in response to mutations in the endoplasmic reticulum degradation machinery. Proc Natl Acad Sci U S A. 2003;100:12735-40 pubmed
    ..By determining the differential abundance of ubiquitinated proteins in yeast mutated for NPL4 and UBC7, which are major components of ER-associated degradation (ERAD), we furthermore were able to classify 83 ..
  13. Pye V, Beuron F, Keetch C, McKeown C, Robinson C, Meyer H, et al. Structural insights into the p97-Ufd1-Npl4 complex. Proc Natl Acad Sci U S A. 2007;104:467-72 pubmed
    ..The two most characterized adaptors for p97 are p47 and the Ufd1 (ubiquitin fusion degradation 1)-Npl4 (nuclear protein localization 4) complex...
  14. Lin K, McDonald K, Guise A, Chan A, Cristea I, Zakian V. Proteomics of yeast telomerase identified Cdc48-Npl4-Ufd1 and Ufd4 as regulators of Est1 and telomere length. Nat Commun. 2015;6:8290 pubmed publisher
    ..known subunits, over 100 proteins are telomerase associated, including all three subunits of the essential Cdc48-Npl4-Ufd1 complex as well as three E3 ubiquitin ligases...
  15. Goder V, Carvalho P, Rapoport T. The ER-associated degradation component Der1p and its homolog Dfm1p are contained in complexes with distinct cofactors of the ATPase Cdc48p. FEBS Lett. 2008;582:1575-80 pubmed publisher
    ..These data suggest distinct functions for the Der1p and Dfm1p complexes. ..
  16. Metzger M, Maurer M, Dancy B, Michaelis S. Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery. J Biol Chem. 2008;283:32302-16 pubmed publisher
    ..In addition, we show a role for the Cdc48p-Npl4p-Ufd1p complex in the degradation of Ura3p-CL1...
  17. Denic V, Quan E, Weissman J. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell. 2006;126:349-59 pubmed
  18. Wilson J, Liu Y, Bentivoglio C, Barlowe C. Sel1p/Ubx2p participates in a distinct Cdc48p-dependent endoplasmic reticulum-associated degradation pathway. Traffic. 2006;7:1213-23 pubmed
    ..of Sel1p from detergent-solubilized ER microsomes revealed a protein complex containing both Cdc48p and Npl4p and suggested a direct role for Sel1p in ERAD...
  19. Cao K, Nakajima R, Meyer H, Zheng Y. The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cell. 2003;115:355-67 pubmed
    ..Here, we report that the AAA-ATPase Cdc48/p97 and its adapters Ufd1-Npl4, which have a well-established role in membrane functions, also regulate spindle disassembly by modulating ..
  20. Verma R, Oania R, Kolawa N, Deshaies R. Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. elife. 2013;2:e00308 pubmed publisher
    ..Here we show that the ubiquitin (Ub) pathway segregase Cdc48/p97 and its adaptors Ufd1-Npl4 participate in ribosome-associated degradation (RAD) by mediating the clearance of ubiquitinated, tRNA-linked ..