SGTA Recognizes a Noncanonical Ubiquitin-like Domain in the Bag6-Ubl4A-Trc35 Complex to Promote Endoplasmic Reticulum-associated Degradation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2012 Dec 19

PMID 23246001

Citations 62

Authors

Yue Xu

Mengli Cai

Yingying Yang

Lan Huang

Yihong Ye

Affiliations

Soon will be listed here.

Abstract

Elimination of aberrantly folded polypeptides from the endoplasmic reticulum (ER) by the ER-associated degradation (ERAD) system promotes cell survival under stress conditions. This quality control mechanism requires movement of misfolded proteins across the ER membrane for targeting to the cytosolic proteasome, a process facilitated by a "holdase" complex, consisting of Bag6 and the cofactors Ubl4A and Trc35. This multiprotein complex also participates in several other protein quality control processes. Here, we report SGTA as a component of the Bag6 system, which cooperates with Bag6 to channel dislocated ERAD substrates that are prone to aggregation. Using nuclear magnetic resonance spectroscopy and biochemical assays, we demonstrate that SGTA contains a noncanonical ubiquitin-like-binding domain that interacts specifically with an unconventional ubiquitin-like protein/domain in Ubl4A at least in part via electrostatics. This interaction helps recruit SGTA to Bag6, enhances substrate loading to Bag6, and thus prevents the formation of nondegradable protein aggregates in ERAD.

Citing Articles

GdX inhibits the occurrence and progression of breast cancer by negatively modulating the activity of STAT3.

Chen Z, Xu L, Lin S, Huang H, Long Q, Liu J Cancer Biol Ther. 2024; 25(1):2420383.

PMID: 39487760 PMC: 11540090. DOI: 10.1080/15384047.2024.2420383.

HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains.

Kamada Y, Ohnishi Y, Nakashima C, Fujii A, Terakawa M, Hamano I J Cell Biol. 2024; 223(7).

PMID: 38722278 PMC: 11082371. DOI: 10.1083/jcb.202308003.

Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.

Katsuki R, Kanuka M, Ohta R, Yoshida S, Tamura T Genes Cells. 2024; 29(6):486-502.

PMID: 38682256 PMC: 11163939. DOI: 10.1111/gtc.13117.

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.

Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.

Chen G, Wei T, Ju F, Li H Front Cell Dev Biol. 2023; 11:1156152.

PMID: 37152279 PMC: 10154544. DOI: 10.3389/fcell.2023.1156152.

References

Hessa T, Sharma A, Mariappan M, Eshleman H, Gutierrez E, Hegde R . Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature. 2011; 475(7356):394-7. PMC: 3150218. DOI: 10.1038/nature10181. View

Minami R, Hayakawa A, Kagawa H, Yanagi Y, Yokosawa H, Kawahara H . BAG-6 is essential for selective elimination of defective proteasomal substrates. J Cell Biol. 2010; 190(4):637-50. PMC: 2928017. DOI: 10.1083/jcb.200908092. 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

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

Kim W, Spear E, Ng D . Yos9p detects and targets misfolded glycoproteins for ER-associated degradation. Mol Cell. 2005; 19(6):753-64. DOI: 10.1016/j.molcel.2005.08.010. View

Prag G, Misra S, Jones E, Ghirlando R, Davies B, Horazdovsky B . Mechanism of ubiquitin recognition by the CUE domain of Vps9p. Cell. 2003; 113(5):609-20. DOI: 10.1016/s0092-8674(03)00364-7. 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

Husnjak K, Dikic I . Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem. 2012; 81:291-322. DOI: 10.1146/annurev-biochem-051810-094654. View

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

10.

Chartron J, VanderVelde D, Clemons Jr W . Structures of the Sgt2/SGTA dimerization domain with the Get5/UBL4A UBL domain reveal an interaction that forms a conserved dynamic interface. Cell Rep. 2012; 2(6):1620-32. PMC: 3654831. DOI: 10.1016/j.celrep.2012.10.010. View

11.

Leznicki P, Clancy A, Schwappach B, High S . Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010; 123(Pt 13):2170-8. PMC: 2886740. DOI: 10.1242/jcs.066738. View

12.

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

13.

Meusser B, Hirsch C, Jarosch E, Sommer T . ERAD: the long road to destruction. Nat Cell Biol. 2005; 7(8):766-72. DOI: 10.1038/ncb0805-766. View

14.

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

15.

Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan R . A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010; 466(7310):1120-4. PMC: 2928861. DOI: 10.1038/nature09296. View

16.

Garrett D, Powers R, Gronenborn A, Clore G . A common sense approach to peak picking in two-, three-, and four-dimensional spectra using automatic computer analysis of contour diagrams. 1991. J Magn Reson. 2011; 213(2):357-63. DOI: 10.1016/j.jmr.2011.09.007. View

17.

Clore G, Gronenborn A . Structures of larger proteins in solution: three- and four-dimensional heteronuclear NMR spectroscopy. Science. 1991; 252(5011):1390-9. DOI: 10.1126/science.2047852. View

18.

Bhamidipati A, Denic V, Quan E, Weissman J . Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol Cell. 2005; 19(6):741-51. DOI: 10.1016/j.molcel.2005.07.027. View

19.

Kohl C, Tessarz P, von der Malsburg K, Zahn R, Bukau B, Mogk A . Cooperative and independent activities of Sgt2 and Get5 in the targeting of tail-anchored proteins. Biol Chem. 2011; 392(7):601-8. DOI: 10.1515/BC.2011.066. View

20.

Hoeller D, Hecker C, Dikic I . Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer. 2006; 6(10):776-88. DOI: 10.1038/nrc1994. View