Role of HERP and a HERP-related Protein in HRD1-dependent Protein Degradation at the Endoplasmic Reticulum

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Dec 25

PMID 24366871

Citations 27

Authors

Chih-Hsiang Huang

Yue-Ru Chu

Yihong Ye

Xin Chen

Affiliations

Soon will be listed here.

Abstract

Misfolded proteins of the endoplasmic reticulum (ER) are retrotranslocated to the cytosol and degraded by the proteasome via a process termed ER-associated degradation (ERAD). The precise mechanism of retrotranslocation is unclear. Here, we use several lumenal ERAD substrates targeted for degradation by the ubiquitin ligase HRD1 including SHH (sonic hedgehog) and NHK (null Hong Kong α1-antitrypsin) to study the geometry, organization, and regulation of the HRD1-containing ERAD machinery. We report a new HRD1-associated membrane protein named HERP2, which is homologous to the previously identified HRD1 partner HERP1. Despite sequence homology, HERP2 is constitutively expressed in cells, whereas HERP1 is highly induced by ER stress. We find that these proteins are required for efficient degradation of both glycosylated and nonglycosylated SHH proteins as well as NHK. In cells depleted of HERPs, SHH proteins are largely trapped inside the ER with a fraction of the stabilized SHH protein bound to the HRD1-SEL1L ligase complex. Ubiquitination of SHH is significantly attenuated in the absence of HERPs, suggesting a defect in retrotranslocation. Both HERP proteins interact with HRD1 through a region located in the cytosol. However, unlike its homolog in Saccharomyces cerevisiae, HERPs do not regulate HRD1 stability or oligomerization status. Instead, they help recruit DERL2 to the HRD1-SEL1L complex. Additionally, the UBL domain of HERP1 also seems to have a function independent of DERL2 recruitment in ERAD. Our studies have revealed a critical scaffolding function for mammalian HERP proteins that is required for forming an active retrotranslocation complex containing HRD1, SEL1L, and DERL2.

Citing Articles

Customizable gene sensing and response without altering endogenous coding sequences.

Caliendo F, Vitu E, Wang J, Kuo S, Sandt H, Enghuus C Nat Chem Biol. 2024; 21(3):348-359.

PMID: 39266721 DOI: 10.1038/s41589-024-01733-y.

Promotion of endoplasmic reticulum retrotranslocation by overexpression of E3 ubiquitin-protein ligase synoviolin 1 reduces endoplasmic reticulum stress and preserves cone photoreceptors in cyclic nucleotide-gated channel deficiency.

Yang F, Ma H, Boye S, Boye S, Ding X FASEB J. 2024; 38(17):e70021.

PMID: 39215566 PMC: 11419579. DOI: 10.1096/fj.202400198R.

SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.

Lin L, Wang H, Pederson B, Wei X, Torres M, Lu Y Nat Commun. 2024; 15(1):1440.

PMID: 38365914 PMC: 10873344. DOI: 10.1038/s41467-024-45633-0.

Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress.

Su R, Yin J, Ruan X, Chen Y, Wan P, Luo Z Comput Struct Biotechnol J. 2023; 21:4478-4487.

PMID: 37736299 PMC: 10510068. DOI: 10.1016/j.csbj.2023.09.006.

Mechanisms of substrate processing during ER-associated protein degradation.

Christianson J, Jarosch E, Sommer T Nat Rev Mol Cell Biol. 2023; 24(11):777-796.

PMID: 37528230 DOI: 10.1038/s41580-023-00633-8.

References

Gardner R, Swarbrick G, Bays N, Cronin S, Wilhovsky S, SEELIG L . Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol. 2000; 151(1):69-82. PMC: 2189800. DOI: 10.1083/jcb.151.1.69. View

Gauss R, Jarosch E, Sommer T, Hirsch C . A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol. 2006; 8(8):849-54. DOI: 10.1038/ncb1445. View

Christianson J, Shaler T, Tyler R, Kopito R . OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat Cell Biol. 2008; 10(3):272-82. PMC: 2757077. DOI: 10.1038/ncb1689. View

Kokame K, Agarwala K, Kato H, Miyata T . Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J Biol Chem. 2000; 275(42):32846-53. DOI: 10.1074/jbc.M002063200. View

Vashist S, Ng D . Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J Cell Biol. 2004; 165(1):41-52. PMC: 2172089. DOI: 10.1083/jcb.200309132. View

Shibata Y, Voss C, Rist J, Hu J, Rapoport T, Prinz W . The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J Biol Chem. 2008; 283(27):18892-904. PMC: 2441541. DOI: 10.1074/jbc.M800986200. View

Carroll S, Hampton R . Usa1p is required for optimal function and regulation of the Hrd1p endoplasmic reticulum-associated degradation ubiquitin ligase. J Biol Chem. 2009; 285(8):5146-56. PMC: 2820741. DOI: 10.1074/jbc.M109.067876. View

Taxis C, Hitt R, Park S, Deak P, Kostova Z, Wolf D . Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. J Biol Chem. 2003; 278(38):35903-13. DOI: 10.1074/jbc.M301080200. View

Carvalho P, Goder V, Rapoport T . Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006; 126(2):361-73. DOI: 10.1016/j.cell.2006.05.043. View

10.

Hori O, Ichinoda F, Yamaguchi A, Tamatani T, Taniguchi M, Koyama Y . Role of Herp in the endoplasmic reticulum stress response. Genes Cells. 2004; 9(5):457-69. DOI: 10.1111/j.1356-9597.2004.00735.x. View

11.

Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E . The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol. 2005; 354(5):1021-7. DOI: 10.1016/j.jmb.2005.10.020. View

12.

Smith M, Ploegh H, Weissman J . Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science. 2011; 334(6059):1086-90. PMC: 3864754. DOI: 10.1126/science.1209235. View

13.

Sato B, Hampton R . Yeast Derlin Dfm1 interacts with Cdc48 and functions in ER homeostasis. Yeast. 2006; 23(14-15):1053-64. DOI: 10.1002/yea.1407. View

14.

Denic V, Quan E, Weissman J . A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell. 2006; 126(2):349-59. DOI: 10.1016/j.cell.2006.05.045. View

15.

Chan S, Fu W, Zhang P, Cheng A, Lee J, Kokame K . Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J Biol Chem. 2004; 279(27):28733-43. DOI: 10.1074/jbc.M404272200. View

16.

Bays N, Gardner R, Seelig L, Joazeiro C, Hampton R . Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol. 2001; 3(1):24-9. DOI: 10.1038/35050524. View

17.

Carvalho P, Stanley A, Rapoport T . Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell. 2010; 143(4):579-91. PMC: 3026631. DOI: 10.1016/j.cell.2010.10.028. View

18.

Kny M, Standera S, Hartmann-Petersen R, Kloetzel P, Seeger M . Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like domain-dependent manner. J Biol Chem. 2010; 286(7):5151-6. PMC: 3037627. DOI: 10.1074/jbc.M110.134551. View

19.

Okuda-Shimizu Y, Hendershot L . Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Mol Cell. 2007; 28(4):544-54. PMC: 2149893. DOI: 10.1016/j.molcel.2007.09.012. View

20.

Brodsky J . Cleaning up: ER-associated degradation to the rescue. Cell. 2012; 151(6):1163-7. PMC: 3521611. DOI: 10.1016/j.cell.2012.11.012. View