{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:59:39Z","timestamp":1792886379220,"version":"4.5.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T00:00:00Z","timestamp":1692057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Ring finger protein 213 (RNF213) is a large E3 ubiquitin ligase with a molecular weight of 591 kDa that is associated with moyamoya disease, a rare cerebrovascular disease. It is located in the cytosol and perinuclear space. Missense mutations in this gene have been found to be more prevalent in patients with moyamoya disease compared with that in healthy individuals. Understanding the molecular function of RNF213 could provide insights into moyamoya disease. RNF213 contains a C3HC4-type RING finger domain with an E3 ubiquitin ligase domain and six AAA+ adenosine triphosphatase (ATPase) domains. It is the only known protein with both AAA+ ATPase and ubiquitin ligase activities. Recent studies have highlighted the role of RNF213 in fighting against microbial infections, including viruses, parasites, bacteria, and chlamydiae. This review aims to summarize the recent research progress on the mechanisms of RNF213 in pathogenic infections, which will aid researchers in understanding the antimicrobial role of RNF213.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1205355","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T04:27:27Z","timestamp":1692246447000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["The emerging role of E3 ubiquitin ligase RNF213 as an antimicrobial host determinant"],"prefix":"10.3389","volume":"13","author":[{"given":"Yulu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leiliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56185","article-title":"Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism","volume":"9","author":"Ahel","year":"2020","journal-title":"Elife"},{"key":"B2","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.molmed.2022.08.009","article-title":"Moyamoya disease emerging as an immune-related angiopathy","volume":"28","author":"Asselman","year":"2022","journal-title":"Trends Mol. Med."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000807","article-title":"MMD-associated RNF213 SNPs encode dominant-negative alleles that globally impair ubiquitylation","volume":"5","author":"Bhardwaj","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00852-20","article-title":"ISG15 connects autophagy and IFN-\u03b3-dependent control of toxoplasma gondii infection in human cells","volume":"11","author":"Bhushan","year":"2020","journal-title":"mBio"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay8085","article-title":"MamMalian lipid droplets are innate immune hubs integrating cell metabolism and host defense","volume":"370","author":"Bosch","year":"2020","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cmet.2009.03.011","article-title":"As a matter of fat","volume":"10","author":"Brookheart","year":"2009","journal-title":"Cell Metab."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7908392","article-title":"The clinical and vascular characteristics of RNF213 c.14576G>A variant-related intracranial major artery disease in China","volume":"2019","author":"Cheng","year":"2019","journal-title":"Behav. Neurol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1102643","article-title":"Lipid droplets as multifunctional organelles related to the mechanism of evasion during mycobacterial infection","volume":"13","author":"de Almeida","year":"2023","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"15623","DOI":"10.1073\/pnas.95.26.15623","article-title":"Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays","volume":"95","author":"Der","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.104549","article-title":"Reversible cerebral angiopathy after viral infection in a pediatric patient with genetic variant of RNF213","volume":"29","author":"Echizenya","year":"2020","journal-title":"J. Stroke Cerebrovasc Dis."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201314","article-title":"Lessons from Toxoplasma: Host responses that mediate parasite control and the microbial effectors that subvert them","volume":"218","author":"Frickel","year":"2021","journal-title":"J. Exp. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1016\/j.chom.2022.11.007","article-title":"GarD-ing the pathogen-containing vacuole from destruction","volume":"30","author":"Gilliland","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1073\/pnas.72.1.11","article-title":"Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells","volume":"72","author":"Goldstein","year":"1975","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1038\/ejhg.2017.92","article-title":"Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians","volume":"25","author":"Guey","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1096\/fba.2019-00092","article-title":"UBC13 is an RNF213-associated E2 ubiquitin-conjugating enzyme, and Lysine 63-linked ubiquitination by the RNF213-UBC13 axis is responsible for angiogenic activity","volume":"3","author":"Habu","year":"2021","journal-title":"FASEB Bioadv"},{"key":"B16","doi-asserted-by":"publisher","first-page":"E5628","DOI":"10.1073\/pnas.1515966112","article-title":"Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins","volume":"112","author":"Haldar","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B17","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.it.2016.11.001","article-title":"ISG15: in sickness and in health","volume":"38","author":"Hermann","year":"2017","journal-title":"Trends Immunol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01888-22","article-title":"Interferon-inducible E3 ligase RNF213 facilitates host-protective linear and K63-linked ubiquitylation of toxoplasma gondii parasitophorous vacuoles","volume":"13","author":"Hernandez","year":"2022","journal-title":"mBio"},{"key":"B19","doi-asserted-by":"publisher","first-page":"555","DOI":"10.3390\/life12040555","article-title":"RNF213-associated vascular disease: A concept unifying various vasculopathies","volume":"12","author":"Hiraide","year":"2022","journal-title":"Life (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1007\/s00335-020-09856-y","article-title":"The ring finger protein 213 gene (Rnf213) contributes to Rift Valley fever resistance in mice","volume":"32","author":"Houzelstein","year":"2021","journal-title":"Mamm Genome"},{"key":"B21","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/s1474-4422(22)00165-x","article-title":"Moyamoya disease: diagnosis and interventions","volume":"21","author":"Ihara","year":"2022","journal-title":"Lancet Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.tcb.2012.04.001","article-title":"Diverse ubiquitin signaling in NF-\u03baB activation","volume":"22","author":"Iwai","year":"2012","journal-title":"Trends Cell Biol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010405","article-title":"ISG15 deficiency restricts HIV-1 infection","volume":"18","author":"Jurczyszak","year":"2022","journal-title":"PloS Pathog."},{"key":"B24","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/jhg.2010.132","article-title":"A genome-wide association study identifies RNF213 as the first Moyamoya disease gene","volume":"56","author":"Kamada","year":"2011","journal-title":"J. Hum. Genet."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.1008175","article-title":"Non-lysine ubiquitylation: Doing things differently","volume":"9","author":"Kelsall","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.115.002146","article-title":"Biochemical and functional characterization of RNF213 (Mysterin) R4810K, a susceptibility mutation of moyamoya disease, in angiogenesis in vitro and in vivo","volume":"4","author":"Kobayashi","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12199-017-0680-1","article-title":"Rare variants of RNF213 and moyamoya\/non-moyamoya intracranial artery stenosis\/occlusion disease risk: a meta-analysis and systematic review","volume":"22","author":"Liao","year":"2017","journal-title":"Environ. Health Prev. Med."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022542","article-title":"Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development","volume":"6","author":"Liu","year":"2011","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.735416","article-title":"Proteome profiling of RNF213 depleted cells reveals nitric oxide regulator DDAH1 antilisterial activity","volume":"11","author":"Martina","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1016\/j.chom.2022.09.017","article-title":"An expanded arsenal of immune systems that protect bacteria from phages","volume":"30","author":"Millman","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuaa066","article-title":"Lipid droplets and lipid mediators in viral infection and immunity","volume":"45","author":"Monson","year":"2021","journal-title":"FEMS Microbiol. Rev."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/srep04442","article-title":"Moyamoya disease-associated protein mysterin\/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state","volume":"4","author":"Morito","year":"2014","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019103758","article-title":"Toxoplasma GRA15 limits parasite growth in IFN\u03b3-activated fibroblasts through TRAF ubiquitin ligases","volume":"39","author":"Mukhopadhyay","year":"2020","journal-title":"EMBO J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"17063","DOI":"10.1038\/nmicrobiol.2017.63","article-title":"LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-\u03baB","volume":"2","author":"Noad","year":"2017","journal-title":"Nat. Microbiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/s41586-021-03566-4","article-title":"Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection","volume":"594","author":"Otten","year":"2021","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3324","DOI":"10.1074\/jbc.272.6.3324","article-title":"Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis","volume":"272","author":"Paumen","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"10286","DOI":"10.3390\/ijms221910286","article-title":"Regulation of O-linked N-acetyl glucosamine transferase (OGT) through E6 stimulation of the ubiquitin ligase activity of E6AP","volume":"22","author":"Peng","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/s41579-018-0020-5","article-title":"ISG15 in antiviral immunity and beyond","volume":"16","author":"Perng","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.molcel.2019.01.036","article-title":"Probing the global cellular responses to lipotoxicity caused by saturated fatty acids","volume":"74","author":"Piccolis","year":"2019","journal-title":"Mol. Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"435","DOI":"10.3390\/genes13030435","article-title":"Network meta-analysis of chicken microarray data following avian influenza challenge-A comparison of highly and lowly pathogenic strains","volume":"13","author":"Pirbaluty","year":"2022","journal-title":"Genes (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"4492","DOI":"10.3390\/ijms23094492","article-title":"Novel multifaceted roles for RNF213 protein","volume":"23","author":"Pollaci","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06848","article-title":"ISG15 counteracts Listeria monocytogenes infection","volume":"4","author":"Radoshevich","year":"2015","journal-title":"Elife"},{"key":"B43","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.tibs.2012.11.007","article-title":"Linear ubiquitination: a newly discovered regulator of cell signalling","volume":"38","author":"Rieser","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1083\/jcb.201712120","article-title":"The AAA+ ATPase\/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets","volume":"218","author":"Sugihara","year":"2019","journal-title":"J. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"607","DOI":"10.2176\/nmc.oa.2017-0036","article-title":"Differences in the genotype frequency of the RNF213 variant in patients with familial moyamoya disease in Kyushu, Japan","volume":"57","author":"Takamatsu","year":"2017","journal-title":"Neurol. Med. Chir (Tokyo)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"7554","DOI":"10.1002\/jcp.30396","article-title":"Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation","volume":"236","author":"Tashiro","year":"2021","journal-title":"J. Cell Physiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"5772","DOI":"10.1038\/s41467-021-26061-w","article-title":"Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity","volume":"12","author":"Thery","year":"2021","journal-title":"Nat. Commun."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2218825120","article-title":"RNF213 modulates \u03b3-herpesvirus infection and reactivation via targeting the viral Replication and Transcription Activator","volume":"120","author":"Tian","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B49","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1093\/jb\/mvt079","article-title":"Linear ubiquitination-mediated NF-\u03baB regulation and its related disorders","volume":"154","author":"Tokunaga","year":"2013","journal-title":"J. Biochem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1016\/j.chom.2022.08.008","article-title":"The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction","volume":"30","author":"Walsh","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B51","doi-asserted-by":"publisher","first-page":"9235","DOI":"10.1016\/S0021-9258(19)52535-2","article-title":"Stimulation of ATP-dependent proteolysis requires ubiquitin with the COOH-terminal sequence Arg-Gly-Gly","volume":"256","author":"Wilkinson","year":"1981","journal-title":"J. Biol. Chem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/s0076-6879(05)99024-1","article-title":"Structure-based approaches to create new E2-E3 enzyme pairs","volume":"399","author":"Winkler","year":"2005","journal-title":"Methods Enzymol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1093\/emboj\/20.3.362","article-title":"Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein","volume":"20","author":"Yuan","year":"2001","journal-title":"EMBO J."},{"key":"B54","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1146\/annurev-biochem-060815-014922","article-title":"Ubiquitin ligases: structure, function, and regulation","volume":"86","author":"Zheng","year":"2017","journal-title":"Annu. Rev. Biochem."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1205355\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T04:27:30Z","timestamp":1692246450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1205355\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,15]]},"references-count":54,"alternative-id":["10.3389\/fcimb.2023.1205355"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2023.1205355","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,15]]},"article-number":"1205355"}}