Gene Symbol: SSM4
Description: E3 ubiquitin-protein ligase SSM4
Alias: DOA10, KIS3, E3 ubiquitin-protein ligase SSM4
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. 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
    ..Interestingly, we also identified novel membrane-bound transcription factors that may be subject to ubiquitin/proteasome-mediated cleavage and activation at the ER membrane. ..
  2. Deng M, Hochstrasser M. Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Nature. 2006;443:827-31 pubmed
    The ubiquitin system targets many cellular proteins. Doa10 (also known as Ssm4), a yeast transmembrane ubiquitin ligase (E3), resides in the endoplasmic reticulum (ER), but it attaches ubiquitin to soluble proteins that concentrate in ..
  3. Adle D, Wei W, Smith N, Bies J, Lee J. Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter. Proc Natl Acad Sci U S A. 2009;106:10189-94 pubmed publisher
    ..ERAD of a portion of secretory proteins might occur via signal-dependent regulatory mechanisms as demonstrated for Pca1. ..
  4. Theodoraki M, Nillegoda N, Saini J, Caplan A. A network of ubiquitin ligases is important for the dynamics of misfolded protein aggregates in yeast. J Biol Chem. 2012;287:23911-22 pubmed publisher
    ..Deletion of UBR1 in combination with LTN1, UFD4, or DOA10 led to a marked hypersensitivity to azetidine 2-carboxylic acid, suggesting some redundancy in the networks of ..
  5. Kota J, Gilstring C, Ljungdahl P. Membrane chaperone Shr3 assists in folding amino acid permeases preventing precocious ERAD. J Cell Biol. 2007;176:617-28 pubmed
    ..We also show that Doa10- and Hrd1-dependent ER-associated degradation (ERAD) pathways redundantly degrade AAP aggregates...
  6. Ravid T, Kreft S, Hochstrasser M. Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J. 2006;25:533-43 pubmed
    The yeast Doa10 ubiquitin (Ub) ligase resides in the endoplasmic reticulum (ER)/nuclear envelope (NE), where it functions in ER-associated degradation (ERAD)...
  7. 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. ..
  8. Hrizo S, Gusarova V, Habiel D, Goeckeler J, Fisher E, Brodsky J. The Hsp110 molecular chaperone stabilizes apolipoprotein B from endoplasmic reticulum-associated degradation (ERAD). J Biol Chem. 2007;282:32665-75 pubmed
    ..This study indicates that chaperones within distinct complexes can play unique roles during ER-associated degradation (ERAD), establishes a role for Sse1/Hsp110 in ERAD, and identifies Hsp110 as a target to lower cholesterol. ..
  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
    ..Ubx2 (Sel1) mediates interaction of the Cdc48 complex with the ER membrane-bound ubiquitin ligases Hrd1 (Der3) and Doa10. The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain...

More Information


  1. Swanson R, Locher M, Hochstrasser M. A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev. 2001;15:2660-74 pubmed
    ..Here we identify Doa10/Ssm4 as a yeast E3 that is embedded in the endoplasmic reticulum (ER)/nuclear envelope yet can target the soluble ..
  2. Xie Y, Rubenstein E, Matt T, Hochstrasser M. SUMO-independent in vivo activity of a SUMO-targeted ubiquitin ligase toward a short-lived transcription factor. Genes Dev. 2010;24:893-903 pubmed publisher
    ..We suggest that alpha2, and presumably other proteins, have surface features that mimic SUMO, and therefore can directly recruit STUbLs without prior SUMO conjugation. ..
  3. Furth N, Gertman O, Shiber A, Alfassy O, Cohen I, Rosenberg M, et al. Exposure of bipartite hydrophobic signal triggers nuclear quality control of Ndc10 at the endoplasmic reticulum/nuclear envelope. Mol Biol Cell. 2011;22:4726-39 pubmed publisher
    ..These findings substantiate the ability of the ER quality control system to recognize subtle perturbation(s) in the native structure of a nuclear protein. ..
  4. Stolz A, Besser S, Hottmann H, Wolf D. Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation. Proc Natl Acad Sci U S A. 2013;110:15271-6 pubmed publisher
    ..membrane-embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome...
  5. Huyer G, Piluek W, Fansler Z, Kreft S, Hochstrasser M, Brodsky J, et al. Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J Biol Chem. 2004;279:38369-78 pubmed
  6. Kreft S, Hochstrasser M. An unusual transmembrane helix in the endoplasmic reticulum ubiquitin ligase Doa10 modulates degradation of its cognate E2 enzyme. J Biol Chem. 2011;286:20163-74 pubmed publisher
    ..Yeast Doa10 is a polytopic membrane ubiquitin ligase (E3) that along with its cognate ubiquitin-conjugating enzymes (E2s), ..
  7. Mandart E, Dufour M, Lacroute F. Inactivation of SSM4, a new Saccharomyces cerevisiae gene, suppresses mRNA instability due to rna14 mutations. Mol Gen Genet. 1994;245:323-33 pubmed
    ..Mutations in a single locus, named SSM4, not only suppress the cell growth phenotype but also the mRNA instability and extend the short mRNA poly(A) tails...
  8. Kreft S, Wang L, Hochstrasser M. Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J Biol Chem. 2006;281:4646-53 pubmed
    ..b>Doa10, a transmembrane protein of the ER/nuclear envelope, is one of the primary ubiquitin ligases (E3s) participating ..
  9. Nakatsukasa K, Huyer G, Michaelis S, Brodsky J. Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell. 2008;132:101-12 pubmed publisher
    ..These data indicate that polytopic membrane proteins can be extracted from the ER, and define the point of action of chaperones and the requirement for Ufd2p during membrane protein quality control...
  10. Loertscher J, Larson L, Matson C, Parrish M, Felthauser A, Sturm A, et al. Endoplasmic reticulum-associated degradation is required for cold adaptation and regulation of sterol biosynthesis in the yeast Saccharomyces cerevisiae. Eukaryot Cell. 2006;5:712-22 pubmed
    ..We have discovered that the ERAD proteins Ubc7 (Qri8), Cue1, and Doa10 (Ssm4) are required for growth of yeast that express high levels of the sterol biosynthetic enzyme, 3-hydroxy-3-..
  11. Foresti O, Ruggiano A, Hannibal Bach H, Ejsing C, Carvalho P. Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. elife. 2013;2:e00953 pubmed publisher
    ..This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein ..
  12. Mitchell D, Hamel L, Ishizuka K, Mitchell G, Schaefer L, Deschenes R. The Erf4 subunit of the yeast Ras palmitoyl acyltransferase is required for stability of the Acyl-Erf2 intermediate and palmitoyl transfer to a Ras2 substrate. J Biol Chem. 2012;287:34337-48 pubmed publisher
    ..This is the first demonstration of regulation of a DHHC PAT enzyme by an associated protein. ..
  13. Needham P, Mikoluk K, Dhakarwal P, Khadem S, Snyder A, Subramanya A, et al. The thiazide-sensitive NaCl cotransporter is targeted for chaperone-dependent endoplasmic reticulum-associated degradation. J Biol Chem. 2011;286:43611-21 pubmed publisher
    ..Together, these results provide the first survey of components involved in the ERAD of a mammalian SLC12 cation chloride cotransporter and provide a framework for future studies on NCC ER quality control. ..
  14. Liu C, van Dyk D, Xu P, Choe V, Pan H, Peng J, et al. Ubiquitin chain elongation enzyme Ufd2 regulates a subset of Doa10 substrates. J Biol Chem. 2010;285:10265-72 pubmed publisher
    ..We found that the ubiquitin-protein E3 ligase for overexpressed Pex29 is Doa10, which is known to be involved in protein quality control...
  15. Shiber A, Breuer W, Brandeis M, Ravid T. Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting. Mol Biol Cell. 2013;24:2076-87 pubmed publisher
    ..Accordingly, diminished Hsp70 levels, as observed in aging or certain pathological conditions, might be sufficient to trigger ubiquitin-dependent sequestration of partially misfolded proteins into inclusion bodies. ..
  16. Mandart E, Parker R. Effects of mutations in the Saccharomyces cerevisiae RNA14, RNA15, and PAP1 genes on polyadenylation in vivo. Mol Cell Biol. 1995;15:6979-86 pubmed
    ..This alteration in poly(A) site choice in the rna14 mutant can be corrected by the ssm4 suppressor, indicating that this suppression acts at the level of polyadenylation and not by slowing mRNA ..
  17. Buck T, Kolb A, Boyd C, Kleyman T, Brodsky J. The endoplasmic reticulum-associated degradation of the epithelial sodium channel requires a unique complement of molecular chaperones. Mol Biol Cell. 2010;21:1047-58 pubmed publisher
    ..Our data indicate that Hsp40s can act independently of Hsp70 to select substrates for ERAD. ..
  18. Habeck G, Ebner F, Shimada Kreft H, Kreft S. The yeast ERAD-C ubiquitin ligase Doa10 recognizes an intramembrane degron. J Cell Biol. 2015;209:261-73 pubmed publisher
    ..In Saccharomyces cerevisiae, the membrane proteins Hrd1 and Doa10 are the predominant ERAD ubiquitin-protein ligases (E3s)...
  19. Rouillard J, Dufour M, Theunissen B, Mandart E, Dujardin G, Lacroute F. SLS1, a new Saccharomyces cerevisiae gene involved in mitochondrial metabolism, isolated as a syntheticlethal in association with an SSM4 deletion. Mol Gen Genet. 1996;252:700-8 pubmed
    b>SSM4 was isolated as a suppressor of rna14-1, a mutant involved in nuclear mRNA maturation. In order to isolate genes interacting with SSM4, we have searched for mutants that are syntheticlethal in association with an SSM4 deletion...
  20. Zattas D, Berk J, Kreft S, Hochstrasser M. A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation. J Biol Chem. 2016;291:12105-18 pubmed publisher
    ..cerevisiae, two principal ER-associated protein degradation ubiquitin ligases (E3s) reside in the ER membrane, Doa10 and Hrd1...
  21. Bagola K, von Delbrück M, Dittmar G, Scheffner M, Ziv I, Glickman M, et al. Ubiquitin binding by a CUE domain regulates ubiquitin chain formation by ERAD E3 ligases. Mol Cell. 2013;50:528-39 pubmed publisher
    ..Hence, we demonstrate an unexpected function of a UBD in the regulation of ubiquitin chain synthesis. ..
  22. Khmelinskii A, Blaszczak E, Pantazopoulou M, Fischer B, Omnus D, Le Dez G, et al. Protein quality control at the inner nuclear membrane. Nature. 2014;516:410-3 pubmed publisher
    ..protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc7 (refs 2, 3)...
  23. Ruggiano A, Mora G, Búxo L, Carvalho P. Spatial control of lipid droplet proteins by the ERAD ubiquitin ligase Doa10. EMBO J. 2016;35:1644-55 pubmed publisher
    ..Here, we show that the ERAD ubiquitin ligase Doa10 controls the levels of some LD proteins...
  24. Lewis M, Pelham H. Inefficient quality control of thermosensitive proteins on the plasma membrane. PLoS ONE. 2009;4:e5038 pubmed publisher
    ..In soluble form, these proteins are rapidly degraded upon temperature shift, in part due to the action of the Doa10 and San1 ubiquitin ligases and the proteasome. When tethered to the ER protein Use1, they are also degraded...
  25. Ng W, Sergeyenko T, Zeng N, Brown J, Römisch K. Characterization of the proteasome interaction with the Sec61 channel in the endoplasmic reticulum. J Cell Sci. 2007;120:682-91 pubmed
    ..Mutations in the ATP-binding sites of individual Rpt proteins all reduced the affinity of 19S complexes for the ER, suggesting that the 19S base in the ATP-bound conformation docks at the Sec61 channel. ..
  26. Avci D, Fuchs S, Schrul B, Fukumori A, Breker M, Frumkin I, et al. The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance. Mol Cell. 2014;56:630-40 pubmed publisher
    ..Our work shows that Ypf1 functionally interacts with the ER-associated degradation (ERAD) factors Dfm1 and Doa10 to regulate the abundance of nutrient transporters by degradation...
  27. Rubenstein E, Kreft S, Greenblatt W, Swanson R, Hochstrasser M. Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase. J Cell Biol. 2012;197:761-73 pubmed publisher
    ..Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets ..
  28. Laribee R, Shibata Y, Mersman D, Collins S, Kemmeren P, Roguev A, et al. CCR4/NOT complex associates with the proteasome and regulates histone methylation. Proc Natl Acad Sci U S A. 2007;104:5836-41 pubmed
    ..These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome. ..
  29. Cohen I, Wiener R, Reiss Y, Ravid T. Distinct activation of an E2 ubiquitin-conjugating enzyme by its cognate E3 ligases. Proc Natl Acad Sci U S A. 2015;112:E625-32 pubmed publisher
    ..Yeast ERAD employs two integral ER membrane E3 Ub ligases: Hrd1 (also termed "Der3") and Doa10, which recognize a distinct set of substrates...
  30. 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
    ..Moreover, Ubx2 mediates binding of Cdc48 to the ubiquitin ligases Hrd1 and Doa10, and to ERAD substrates...
  31. Stolz A, Schweizer R, Schafer A, Wolf D. Dfm1 forms distinct complexes with Cdc48 and the ER ubiquitin ligases and is required for ERAD. Traffic. 2010;11:1363-9 pubmed publisher
    ..Dfm1 to be part of complexes which contain the ERAD-L ligase Hrd1/Der3 and Der1 as well as the ERAD-C ligase Doa10. In addition, ERAD of Ste6(*)-HA(3) was strongly dependent on Dfm1...
  32. Weber A, Cohen I, Popp O, Dittmar G, Reiss Y, Sommer T, et al. Sequential Poly-ubiquitylation by Specialized Conjugating Enzymes Expands the Versatility of a Quality Control Ubiquitin Ligase. Mol Cell. 2016;63:827-39 pubmed publisher
    The Doa10 quality control ubiquitin (Ub) ligase labels proteins with uniform lysine 48-linked poly-Ub (K48-pUB) chains for proteasomal degradation. Processing of Doa10 substrates requires the activity of two Ub conjugating enzymes...