9g08

Structural highlights

Disease

RN213_HUMAN Moyamoya disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. A chromosomal aberration involving RNF213 is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALK.^[1]

Function

RN213_HUMAN Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity (PubMed:21799892, PubMed:26126547, PubMed:26278786, PubMed:26766444, PubMed:30705059, PubMed:32139119, PubMed:34012115). Acts as a key immune sensor by catalyzing ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS) via its RZ-type zinc-finger: restricts the proliferation of cytosolic bacteria, such as Salmonella, by generating the bacterial ubiquitin coat through the ubiquitination of LPS (PubMed:34012115). Also acts indirectly by mediating the recruitment of the LUBAC complex, which conjugates linear polyubiquitin chains (PubMed:34012115). Ubiquitination of LPS triggers cell-autonomous immunity, such as antibacterial autophagy, leading to degradation of the microbial invader (PubMed:34012115). Involved in lipid metabolism by regulating fat storage and lipid droplet formation; act by inhibiting the lipolytic process (PubMed:30705059). Also regulates lipotoxicity by inhibiting desaturation of fatty acids (PubMed:30846318). Also acts as an E3 ubiquitin-protein ligase via its RING-type zinc finger: mediates 'Lys-63'-linked ubiquitination of target proteins (PubMed:32139119, PubMed:33842849). Involved in the non-canonical Wnt signaling pathway in vascular development: acts by mediating ubiquitination and degradation of FLNA and NFATC2 downstream of RSPO3, leading to inhibit the non-canonical Wnt signaling pathway and promoting vessel regression (PubMed:26766444). Also has ATPase activity; ATPase activity is required for ubiquitination of LPS (PubMed:34012115).^{[2] [3] [4] [5] [6] [7] [8] [9] [10]}

References

1. ↑ Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer. 2002 Aug;34(4):354-62. PMID:12112524 doi:10.1002/gcc.10033
2. ↑ Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542. PMID:21799892 doi:10.1371/journal.pone.0022542
3. ↑ Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Habu T, Takagi Y, Miyamoto S, Koizumi A. Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. J Am Heart Assoc. 2015 Jun 30;4(7):e002146. PMID:26126547 doi:10.1161/JAHA.115.002146
4. ↑ Ohkubo K, Sakai Y, Inoue H, Akamine S, Ishizaki Y, Matsushita Y, Sanefuji M, Torisu H, Ihara K, Sardiello M, Hara T. Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci Rep. 2015 Aug 17;5:13191. PMID:26278786 doi:10.1038/srep13191
5. ↑ Scholz B, Korn C, Wojtarowicz J, Mogler C, Augustin I, Boutros M, Niehrs C, Augustin HG. Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling. Dev Cell. 2016 Jan 11;36(1):79-93. PMID:26766444 doi:10.1016/j.devcel.2015.12.015
6. ↑ Sugihara M, Morito D, Ainuki S, Hirano Y, Ogino K, Kitamura A, Hirata H, Nagata K. The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol. 2019 Mar 4;218(3):949-960. PMID:30705059 doi:10.1083/jcb.201712120
7. ↑ Piccolis M, Bond LM, Kampmann M, Pulimeno P, Chitraju C, Jayson CBK, Vaites LP, Boland S, Lai ZW, Gabriel KR, Elliott SD, Paulo JA, Harper JW, Weissman JS, Walther TC, Farese RV Jr. Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids. Mol Cell. 2019 Apr 4;74(1):32-44.e8. PMID:30846318 doi:10.1016/j.molcel.2019.01.036
8. ↑ Takeda M, Tezuka T, Kim M, Choi J, Oichi Y, Kobayashi H, Harada KH, Mizushima T, Taketani S, Koizumi A, Youssefian S. Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner. Biochem Biophys Res Commun. 2020 May 7;525(3):668-674. PMID:32139119 doi:10.1016/j.bbrc.2020.02.024
9. ↑ Habu T, Harada KH. UBC13 is an RNF213-associated E2 ubiquitin-conjugating enzyme, and Lysine 63-linked ubiquitination by the RNF213-UBC13 axis is responsible for angiogenic activity. FASEB Bioadv. 2021 Jan 20;3(4):243-258. PMID:33842849 doi:10.1096/fba.2019-00092
10. ↑ Otten EG, Werner E, Crespillo-Casado A, Boyle KB, Dharamdasani V, Pathe C, Santhanam B, Randow F. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature. 2021 Jun;594(7861):111-116. PMID:34012115 doi:10.1038/s41586-021-03566-4