DOI: 10.1101/gad.933301. A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matα2 repressor degradation

A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matα2 repressor degradation

10.1101/gad.933301

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

Substrate discrimination in the ubiquitin–proteasome system is believed to be dictated by specific combinations of ubiquitin–protein ligases (E3s) and ubiquitin-conjugating enzymes (E2s). Here we identify Doa10/Ssm4 as a yeast E3 that is embedded in the endoplasmic reticulum (ER)/nuclear envelope yet can target the soluble transcription factor Matα2. Doa10 contains an unusual RING finger, which has ubiquitin-ligase activity in vitro and is essential in vivo for degradation of α2 via its Deg1 degradation signal. Doa10 functions with two E2s, Ubc6 and Ubc7, to ubiquitinateDeg1-bearing substrates, and it is also required for the degradation of at least one ER membrane protein. Interestingly, different short-lived ER proteins show distinct requirements for Doa10 and another ER-localized E3, Hrd1. Nevertheless, the two E3s overlap in function: A doa10Δ hrd1Δ mutant is far more sensitive to cadmium relative to either single mutant and displays strong constitutive induction of the unfolded protein response; this suggests a role for both E3s in eliminating aberrant ER proteins. The likely human ortholog of DOA10 is in the cri-du-chat syndrome critical region on chromosome 5p, suggesting that defective ubiquitin ligation might contribute to this common genetic disorder.

Bibliography

Swanson, R., Locher, M., & Hochstrasser, M. (2001). A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and MatÎ±2 repressor degradation. Genes & Development, 15(20), 2660â2674.

Authors 3

Robert Swanson (first)
Martin Locher (additional)
Mark Hochstrasser (additional)

References 45 Referenced 402

Ausubel F.M. Brent R. Kingston R.E. Moore D.D. Seidman J.G. Smith J.A. Struhl K. (1989) Current protocols in molecular biology. (Wiley, New York, NY).
10.1002/j.1460-2075.1990.tb07516.x / EMBO J. / The recognition component of the N-end rule pathway. by Bartel (1990)
10.1093/nar/21.14.3329
10.1038/35050524
10.1126/science.292.5521.1552
10.1126/science.278.5344.1806
10.1074/jbc.M002479200
10.1016/0092-8674(93)90426-Q
10.1038/35017001
10.1016/0378-1119(88)90185-0
10.1093/emboj/17.10.2759
10.1093/emboj/19.4.550
10.1126/science.273.5282.1725
10.1146/annurev.genet.30.1.405
10.1098/rstb.1999.0495
10.1016/S0092-8674(01)00407-X
10.1016/S0092-8674(00)81421-X
10.1016/S1074-5521(01)00005-9
10.1038/ng0197-70
10.1016/S0092-8674(00)80752-7
10.1128/MCB.20.7.2367-2377.2000
10.1046/j.1432-1327.2001.02227.x / Eur. J. Biochem. / Regulation of p53 localization. by Liang (2001)
10.1002/(SICI)1097-0061(199807)14:10<953::AID-YEA293>3.0.CO;2-U
10.1073/pnas.96.20.11364
10.1126/science.252.5009.1162
10.1136/jmg.38.3.151
10.1007/BF00290112
10.1016/S0014-5793(99)00467-6
10.1016/0378-1119(95)00037-7
10.1128/jvi.71.3.1963-1974.1997 / J. Virol. / A single 13-kilobase divergent locus in the Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genome contains nine open reading frames that are homologous to or related to cellular proteins. by Nicholas (1997)
10.1146/annurev.biochem.70.1.503
10.1016/S0968-0004(99)01420-6
10.1016/S0021-9258(18)81630-1 / J. Biol. Chem. / Binding sites of ubiquitin–protein ligase: Binding of ubiquitin–protein conjugates and of ubiquitin-carrier protein. by Reiss (1989)
10.1083/jcb.153.1.47
10.1007/PL00008653
10.1093/genetics/122.1.19 / Genetics / A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. by Sikorski (1989)
10.1091/mbc.10.8.2583
10.1016/S0014-5793(00)01802-0
10.1016/S0092-8674(00)80835-1
10.1016/S0968-0004(97)01122-5
10.1093/emboj/20.12.3124
10.1038/35056563
10.1091/mbc.11.5.1697
10.1007/s002320001096
10.1016/S0092-8674(00)00057-X

Dates

Type	When
Created	23 years ago (July 26, 2002, 8 p.m.)
Deposited	3 years, 9 months ago (Nov. 15, 2021, 10:48 a.m.)
Indexed	3 days ago (Aug. 19, 2025, 5:58 a.m.)
Issued	23 years, 10 months ago (Oct. 15, 2001)
Published	23 years, 10 months ago (Oct. 15, 2001)
Published Online	23 years, 10 months ago (Oct. 15, 2001)
Published Print	23 years, 10 months ago (Oct. 15, 2001)

Funders 0

None

BibTeX

@article{Swanson_2001, title={A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matα2 repressor degradation}, volume={15}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.933301}, DOI={10.1101/gad.933301}, number={20}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Swanson, Robert and Locher, Martin and Hochstrasser, Mark}, year={2001}, month=oct, pages={2660–2674} }

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