8.A.133. The SIAH1 E3 ubiquitin-protein ligase (SIAH1) Family E3 ubiquitin-protein ligase, Siah1, mediates ubiquitination and subsequent proteasomal degradation of many target proteins (Hu and Fearon 1999). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (Germani et al. 2003). It interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway (Kim et al. 2004). It has some overlapping function with SIAH2 (Pérez et al. 2012; Malz et al. 2012). It also stabilizes or destabilizes various protein targets (Liu et al. 2012). A review focuses on potential multiprotein complexes involving calcium-insensitive S100A10, annexin A2 and several other proteins including AHNAK, dysferlin, NS3, TASK-1 and TRPV5/6 (Rezvanpour and Shaw 2009). The E3 ligase TRIM7 suppresses the tumorigenesis of gastric cancer by targeting the SLC7A11 cystine/glutamate amino acid transporter (TC# 2.A.3.8.18) (Chen et al. 2024).
References:
Cai, G., L. Zhu, X. Chen, K. Sun, C. Liu, G.C. Sen, G.R. Stark, J. Qin, and X. Li. (2018). TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc. Natl. Acad. Sci. USA 115: 11531-11536.
Chen, Q., T. Zhang, R. Zeng, K. Zhang, B. Li, Z. Zhu, X. Ma, Y. Zhang, L. Li, J. Zhu, and G. Zhang. (2024). The E3 ligase TRIM7 suppresses the tumorigenesis of gastric cancer by targeting SLC7A11. Sci Rep 14: 6655.
Czechowicz, J.S., C.H. Nagel, M. Voges, M. Spohn, M.M. Eibl, and J. Hauber. (2018). Interaction between the cellular E3 ubiquitin ligase SIAH-1 and the viral immediate-early protein ICP0 enables efficient replication of Herpes Simplex Virus type 2 in vivo. PLoS One 13: e0201880.
Fan, W., K.B. Mar, L. Sari, I.K. Gaszek, Q. Cheng, B.M. Evers, J.M. Shelton, M. Wight-Carter, D.J. Siegwart, M.M. Lin, and J.W. Schoggins. (2021). TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity. Cell 184: 3410-3425.e17.
Germani, A., A. Prabel, S. Mourah, M.P. Podgorniak, A. Di Carlo, R. Ehrlich, S. Gisselbrecht, N. Varin-Blank, F. Calvo, and H. Bruzzoni-Giovanelli. (2003). SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway. Oncogene 22: 8845-8851.
Hu, G. and E.R. Fearon. (1999). Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Mol. Cell Biol. 19: 724-732.
Kim, H., W. Jeong, K. Ahn, C. Ahn, and S. Kang. (2004). Siah-1 interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway. J Am Soc Nephrol 15: 2042-2049.
Li, J., P. Wang, Z. Xie, S. Wang, S. Cen, M. Li, W. Liu, S. Tang, G. Ye, G. Zheng, H. Su, M. Ma, X. Wu, Y. Wu, and H. Shen. (2019). TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2. Cell Death Differ 26: 2652-2666.
Liang, X., J. Xiao, X. Li, Y. Liu, Y. Lu, Y. Wen, Z. Li, X. Che, Y. Ma, X. Zhang, Y. Zhang, D. Jian, P. Wang, C. Xuan, G. Yu, L. Li, and H. Zhang. (2022). A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures. Nat Chem Biol 18: 1214-1223.
Liu, M., J. Hsu, C. Chan, Z. Li, and Q. Zhou. (2012). The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription. Mol. Cell 46: 325-334.
Malz, M., A. Aulmann, J. Samarin, M. Bissinger, T. Longerich, S. Schmitt, P. Schirmacher, and K. Breuhahn. (2012). Nuclear accumulation of seven in absentia homologue-2 supports motility and proliferation of liver cancer cells. Int J Cancer 131: 2016-2026.
Pérez, M., C. García-Limones, I. Zapico, A. Marina, M.L. Schmitz, E. Muñoz, and M.A. Calzado. (2012). Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J Mol. Cell Biol. 4: 316-330.
Rezvanpour, A. and G.S. Shaw. (2009). Unique S100 target protein interactions. Gen Physiol Biophys 28SpecNoFocus: F39-46.
Zhang, M., X. Guan, Z. Dong, C. Yang, C. Xiong, W. Cheng, A. Shang, Y. Liu, X. Guo, B. Zhang, B. Zhang, S. Jin, W. Qi, B.T. Alexandrovna, Y. Jiang, Z. Du, and C. Xu. (2025). Targeting Zfp36 to combat cardiac hypertrophy: Insights into ferroptosis pathways. Clin Transl Med 15: e70247.
Zhang, X., X. Wang, J. Chen, M. Chen, X. Lu, J. Ning, H. Liu, G. Liu, X. Xu, X. Qu, K. Yu, H. Xu, C. Wang, and B. Liu. (2024). Functional analyses of TRAF6 gene in Argopecten scallops. Fish Shellfish Immunol 147: 109443.
Examples:
TC#	Name	Organismal Type	Example
8.A.133.1.1	Siah-1 of 282 aas. It plays roles in the stability and degradation of many proteins (Czechowicz et al. 2018). These include polycystin-1, TrpVs and several other transporters (see family description).		Siah-1 on Homo sapiens

8.A.133.1.10	Uncharacterized protein of 596 aas and 4 C-terminal TMSs in a 2 + 2 TMS arrangement.		UP of Fragilariopsis cylindrus

8.A.133.1.11	TNF receptor-associated factor 4, TRAF4, of 470 aas and 0 TMSs. It is an adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, platelet activation and apoptosis (Cai et al. 2018). It ubiquitinates SMURF2 through 'Lys-48'-linked ubiquitin chain, leading to SMURF2 degradation through the proteasome and subsequently osteogenic differentiation (Li et al. 2019). It has an N-terminal domain similar to those of members of this family, but it has a C-terminal domain similar to sheddases such as that in TC# 8.A.77.2.1.		TRAF4 of Homo sapiens

8.A.133.1.12	*Tumor necrosis factor receptor 6 of 681 aas and 0 TMSs. TRAF6 is a key molecular link in the TNF superfamily. Zhang et al.* 2024 conducted a series of studies targeting the TRAF6 gene.**		TRAF6 of Argopecten irradians

8.A.133.1.13	E3 ubiquitin-protein ligase, TRIM7, that have both tumor-promoting and tumor-suppressing activities and functions in several biological processes including innate immunity, regulation of ferroptosis as well as cell proliferation and migration (Fan et al. 2021). It also acts as an antiviral effector against multiple viruses by targeting specific viral proteins for ubiquitination and degradation including norovirus NTPase protein or SARS-CoV-2 NSP5 and NSP8 proteins (Liang et al. 2022). TRIM7 suppresses the tumorigenesis of gastric cancer by targeting the SLC7A11 cystine/glutamate amino acid transporter (Chen et al. 2024). Targeting Zfp36 (mRNA decay activator protein) combats cardiac hypertrophy and provides insight into ferroptosis pathways (Zhang et al. 2025).		TRM7 of Homo sapiens

8.A.133.1.2	Siah-2 of 324 aas. Seven in absentia homologue-2 (Siah-2) is a host protein that can act as does Siah-1, but with different protein specificities. It mediates the ubiquitination of proteins and is known for its interaction with them to alter their stabilities as affect several cell functions (Malz et al. 2012).		Siah-2 of Homo sapiens

8.A.133.1.3	E3 ubiquitin-protein ligase SINA-like 9 of 345 aa		*SINA-like 9 protein of Elaeis guineensis* (African oil palm)**

8.A.133.1.4	E3 ubiquitin-protein ligase SINA-like 11 protein of 386 aas and 1 TMS.		*SINA-like protein of Oryza sativa* Japonica Group (Japanese rice)**

8.A.133.1.5	Uncharacterized protein of 270 aas and 2 closely spaced TMSs between residues 66 and 106.		*UP of Xenopus tropicalis* (tropical clawed frog)**

8.A.133.1.6	Uncharacterized protein of 281 aas and 2 possible TMSs.		UP of Aphanomyces euteiches

8.A.133.1.7	Uncharacterized protein of 366 aas and possibly 2 TMSs.		UP of Emiliania huxleyi

8.A.133.1.8	E3 ubiquitin-protein ligase RNF114 of 222 aas and maybe 2 N-terminal TM		Ubiuitin ligase of Microcaecilia unicolor

8.A.133.1.9	Uncharacterized protein of 291 aas and 1 or 2 possible N-terminal TMS(s).		UP of Rhodotorula toruloides