5y3t

Structural highlights

Disease

[SHRPN_MOUSE] Defects in Sharpin are the cause of chronic proliferative dermatitis (cpdm). Cpdm is a spontaneous mutation causing a chronic proliferative dermatitis phenotype, which is characterized histologically by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development. Mice also display lower total and cortical bone mineral content and bone mineral density, trabecular and cortical bone volume, and trabecular number. TNF-alpha-induced NF-kappa-B activation is attenuated due to inability of the LUBAC complex to mediate linear ubiquitination.^{[1] [2] [3] [4] [5] [6] [7]}

Function

[HOIL1_MOUSE] E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. Component of the LUBAC complex which conjugates linear ('M-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Binds polyubiquitin of different linkage types (By similarity). [SHRPN_MOUSE] Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with FAM105B/otulin, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis.^{[8] [9] [10] [11]} [RNF31_MOUSE] E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with otulin, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different linkage types.[UniProtKB:Q96EP0]

References

1. ↑ Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 2007 Jul;8(5):416-21. doi: 10.1038/sj.gene.6364403. Epub 2007 May, 31. PMID:17538631 doi:http://dx.doi.org/10.1038/sj.gene.6364403
2. ↑ Renninger ML, Seymour RE, Whiteley LO, Sundberg JP, Hogenesch H. Anti-IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin-deficient mice. Exp Dermatol. 2010 Mar;19(3):252-8. doi: 10.1111/j.1600-0625.2009.00944.x. Epub, 2009 Jul 23. PMID:19650867 doi:http://dx.doi.org/10.1111/j.1600-0625.2009.00944.x
3. ↑ Liang Y, Seymour RE, Sundberg JP. Inhibition of NF-kappaB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice. J Invest Dermatol. 2011 Jan;131(1):141-9. doi: 10.1038/jid.2010.259. Epub 2010, Sep 2. PMID:20811394 doi:http://dx.doi.org/10.1038/jid.2010.259
4. ↑ Xia T, Liang Y, Ma J, Li M, Gong M, Yu X. Loss-of-function of SHARPIN causes an osteopenic phenotype in mice. Endocrine. 2011 Apr;39(2):104-12. doi: 10.1007/s12020-010-9418-1. Epub 2010 Nov, 11. PMID:21069580 doi:http://dx.doi.org/10.1007/s12020-010-9418-1
5. ↑ Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011 Mar 31;471(7340):591-6. doi: 10.1038/nature09816. PMID:21455173 doi:10.1038/nature09816
6. ↑ Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815. PMID:21455180 doi:10.1038/nature09815
7. ↑ Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814. PMID:21455181 doi:10.1038/nature09814
8. ↑ Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 2007 Jul;8(5):416-21. doi: 10.1038/sj.gene.6364403. Epub 2007 May, 31. PMID:17538631 doi:http://dx.doi.org/10.1038/sj.gene.6364403
9. ↑ Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011 Mar 31;471(7340):591-6. doi: 10.1038/nature09816. PMID:21455173 doi:10.1038/nature09816
10. ↑ Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815. PMID:21455180 doi:10.1038/nature09815
11. ↑ Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814. PMID:21455181 doi:10.1038/nature09814