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Gene Review

HRD1  -  E3 ubiquitin-protein ligase HRD1

Saccharomyces cerevisiae S288c

Synonyms: DER3, ERAD-associated E3 ubiquitin-protein ligase HRD1, HMG-CoA reductase degradation protein 1, YOL013C
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Disease relevance of HRD1


High impact information on HRD1

  • When Hrd1p is uncoupled from the Yos9p surveillance complex, degradation can occur independently of the requirement for glycosylation [2].
  • Hrd1p is required for the degradation and ubiquitination of several ERAD substrates and physically associates with relevant ubiquitin-conjugating enzymes (E2s) [3].
  • Therefore, we propose that Hrd3p acts as a substrate recruitment factor for the Hrd1p ligase complex [4].
  • The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment [4].
  • CPY* overexpression likely saturates the HRD/DER pathway and activates the HIP pathway, so the slowed degradation kinetics of CPY* in a hrd1 Delta strain is restored to a wild-type rate when CPY* is overexpressed [5].

Biological context of HRD1

  • HEK293T cells overexpressing HRD1 showed resistance to ER stress-induced cell death [6].
  • Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation [7].
  • These results suggest that the production of HRD1 is up-regulated to protect against ER stress-induced apoptosis by degrading unfolded proteins accumulated in the ER [8].

Anatomical context of HRD1

  • Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum [9].
  • Rigorous reevaluation of Hrd1p topology demonstrated that the Hrd1p RING-H2 domain is located and functions in the cytosol [10].
  • Notably, another ER transmembrane E3, Hrd1 (also known as Der3), cannot localize efficiently to the inner nuclear membrane [11].

Associations of HRD1 with chemical compounds

  • We substantiated this hypothesis by constructing a mutated form of Der3/Hrd1p replacing the last cysteine of the motif with a serine [12].

Physical interactions of HRD1


Regulatory relationships of HRD1

  • Hrd1p is a UPR-induced ER membrane protein that acts as a ubiquitin ligase (E3) in the ERAD system [6].

Other interactions of HRD1

  • In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound [13].
  • These results suggest that HRD1 and SEL1 are up-regulated by the UPR and contribute to protection against the ER stress-induced cell death by degrading unfolded proteins accumulated in the ER [6].
  • In contrast to Hmg2p-degradation, that of native CYP3A4 does not appear to absolutely require Hrd1p, another component of the ER-associated Ub-ligase complex [14].
  • Der3p was found to be identical with Hrd1p, a protein identified to be necessary for degradation of HMG-CoA reductase [15].
  • 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 [4].


  1. Induction of murine HRD1 in experimental cerebral ischemia. Qi, X., Okuma, Y., Hosoi, T., Kaneko, M., Nomura, Y. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  2. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Denic, V., Quan, E.M., Weissman, J.S. Cell (2006) [Pubmed]
  3. Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Bays, N.W., Gardner, R.G., Seelig, L.P., Joazeiro, C.A., Hampton, R.Y. Nat. Cell Biol. (2001) [Pubmed]
  4. The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. Gauss, R., Sommer, T., Jarosch, E. EMBO J. (2006) [Pubmed]
  5. An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport. Haynes, C.M., Caldwell, S., Cooper, A.A. J. Cell Biol. (2002) [Pubmed]
  6. ER signaling in unfolded protein response. Kaneko, M., Nomura, Y. Life Sci. (2003) [Pubmed]
  7. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. Plemper, R.K., Bordallo, J., Deak, P.M., Taxis, C., Hitt, R., Wolf, D.H. J. Cell. Sci. (1999) [Pubmed]
  8. Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation. Kaneko, M., Ishiguro, M., Niinuma, Y., Uesugi, M., Nomura, Y. FEBS Lett. (2002) [Pubmed]
  9. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. Kikkert, M., Doolman, R., Dai, M., Avner, R., Hassink, G., van Voorden, S., Thanedar, S., Roitelman, J., Chau, V., Wiertz, E. J. Biol. Chem. (2004) [Pubmed]
  10. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. Gardner, R.G., Swarbrick, G.M., Bays, N.W., Cronin, S.R., Wilhovsky, S., Seelig, L., Kim, C., Hampton, R.Y. J. Cell Biol. (2000) [Pubmed]
  11. Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Deng, M., Hochstrasser, M. Nature (2006) [Pubmed]
  12. A RING-H2 finger motif is essential for the function of Der3/Hrd1 in endoplasmic reticulum associated protein degradation in the yeast Saccharomyces cerevisiae. Bordallo, J., Wolf, D.H. FEBS Lett. (1999) [Pubmed]
  13. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Hampton, R.Y., Gardner, R.G., Rine, J. Mol. Biol. Cell (1996) [Pubmed]
  14. Ubiquitin-dependent 26S proteasomal pathway: a role in the degradation of native human liver CYP3A4 expressed in Saccharomyces cerevisiae? Murray, B.P., Correia, M.A. Arch. Biochem. Biophys. (2001) [Pubmed]
  15. Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Bordallo, J., Plemper, R.K., Finger, A., Wolf, D.H. Mol. Biol. Cell (1998) [Pubmed]
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