{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''RanBP-type and C3HC4-type zinc finger-containing protein 1''' (also known as HOIL-1) is a protein that in humans is encoded by the ''RBCK1'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: RBCK1 RanBP-type and C3HC4-type zinc finger containing 1| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=10616| access-date = }}</ref>
The protein encoded by this gene is similar to mouse UIP28/UbcM4 interacting protein. Alternative splicing has been observed at this locus, resulting in distinct isoforms.<ref name="entrez"/>
HOIL-1 is an E3 ubiquitin ligase and a part of the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase generating linear (Met1) polyubiquitin linkages.<ref>{{cite journal | vauthors = Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S, Tokunaga F, Tanaka K, Iwai K | display-authors = 6 | title = A ubiquitin ligase complex assembles linear polyubiquitin chains | journal = The EMBO Journal | volume = 25 | issue = 20 | pages = 4877–4887 | date = October 2006 | pmid = 17006537 | pmc = 1618115 | doi = 10.1038/sj.emboj.7601360 }}</ref> Although HOIL-1 isn’t responsible for the linear ubiquitin generation, it is a necessary component of LUBAC and ensures its proper assembly and function.<ref>{{cite journal | vauthors = Peltzer N, Darding M, Montinaro A, Draber P, Draberova H, Kupka S, Rieser E, Fisher A, Hutchinson C, Taraborrelli L, Hartwig T, Lafont E, Haas TL, Shimizu Y, Böiers C, Sarr A, Rickard J, Alvarez-Diaz S, Ashworth MT, Beal A, Enver T, Bertin J, Kaiser W, Strasser A, Silke J, Bouillet P, Walczak H | display-authors = 6 | title = LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis | journal = Nature | volume = 557 | issue = 7703 | pages = 112–117 | date = May 2018 | pmid = 29695863 | pmc = 5947819 | doi = 10.1038/s41586-018-0064-8 | bibcode = 2018Natur.557..112P }}</ref> Unlike most E3 ubiquitin ligases, HOIL-1 is able to catalyze oxyester bond formation between the C-terminus of a ubiquitin monomer and Ser/Thr of a different protein. This recently discovered function of HOIL-1 has so far been described in the context of MyD88 signaling.<ref>{{cite journal | vauthors = Kelsall IR, Zhang J, Knebel A, Arthur JS, Cohen P | title = The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 27 | pages = 13293–13298 | date = July 2019 | pmid = 31209050 | pmc = 6613137 | doi = 10.1073/pnas.1905873116 | bibcode = 2019PNAS..11613293K | doi-access = free }}</ref> Additionally, a catalytically inactive mutant of HOIL-1 (HOIL-1<sup>C458S</sup>) led to prolonged IKK activation and increase of inflammatory cytokine production by cytotoxic T cells. The proposed mechanism is that the ester-linked ubiquitin chains limit the size of isopeptide-linked (K63 and/or M1) ubiquitin chains.<ref>{{cite journal | vauthors = Petrova T, Zhang J, Nanda SK, Figueras-Vadillo C, Cohen P | title = HOIL-1-catalysed, ester-linked ubiquitylation restricts IL-18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages | journal = The FEBS Journal | volume = 288 | issue = 20 | pages = 5909–5924 | date = October 2021 | pmid = 33932090 | doi = 10.1111/febs.15896 | s2cid = 233472285 | url = https://discovery.dundee.ac.uk/en/publications/243174bc-a4ef-4c29-b6cc-0ba5686f67e0 | doi-access = free }}</ref>
== Clinical significance ==
A family quartet was found with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet single-nucleotide polymorphism (SNP) genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products.<ref>{{cite journal | vauthors = Wang K, Kim C, Bradfield J, Guo Y, Toskala E, Otieno FG, Hou C, Thomas K, Cardinale C, Lyon GJ, Golhar R, Hakonarson H | display-authors = 6 | title = Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement | journal = Genome Medicine | volume = 5 | issue = 7 | pages = 67 | date = 2013 | pmid = 23889995 | pmc = 3971341 | doi = 10.1186/gm471 | doi-access = free }}</ref> Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified.<ref>{{cite journal | vauthors = Nilsson J, Schoser B, Laforet P, Kalev O, Lindberg C, Romero NB, Dávila López M, Akman HO, Wahbi K, Iglseder S, Eggers C, Engel AG, Dimauro S, Oldfors A | display-authors = 6 | title = Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1 | journal = Annals of Neurology | volume = 74 | issue = 6 | pages = 914–919 | date = December 2013 | pmid = 23798481 | doi = 10.1002/ana.23963 | s2cid = 205344695 | doi-access =free }}</ref>
== References == {{reflist}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Martinez-Noel G, Niedenthal R, Tamura T, Harbers K | title = A family of structurally related RING finger proteins interacts specifically with the ubiquitin-conjugating enzyme UbcM4 | journal = FEBS Letters | volume = 454 | issue = 3 | pages = 257–261 | date = July 1999 | pmid = 10431818 | doi = 10.1016/S0014-5793(99)00823-6 | s2cid = 46159115 | doi-access = free }} * {{cite journal | vauthors = Yamanaka K, Ishikawa H, Megumi Y, Tokunaga F, Kanie M, Rouault TA, Morishima I, Minato N, Ishimori K, Iwai K | display-authors = 6 | title = Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2 | journal = Nature Cell Biology | volume = 5 | issue = 4 | pages = 336–340 | date = April 2003 | pmid = 12629548 | doi = 10.1038/ncb952 | s2cid = 20453941 }} * {{cite journal | vauthors = Hillman RT, Green RE, Brenner SE | title = An unappreciated role for RNA surveillance | journal = Genome Biology | volume = 5 | issue = 2 | pages = R8 | year = 2005 | pmid = 14759258 | pmc = 395752 | doi = 10.1186/gb-2004-5-2-r8 | doi-access = free }} * {{cite journal | vauthors = Tatematsu K, Yoshimoto N, Koyanagi T, Tokunaga C, Tachibana T, Yoneda Y, Yoshida M, Okajima T, Tanizawa K, Kuroda S | display-authors = 6 | title = Nuclear-cytoplasmic shuttling of a RING-IBR protein RBCK1 and its functional interaction with nuclear body proteins | journal = The Journal of Biological Chemistry | volume = 280 | issue = 24 | pages = 22937–22944 | date = June 2005 | pmid = 15833741 | doi = 10.1074/jbc.M413476200 | doi-access = free }} * {{cite journal | vauthors = Zhang Y, Wolf-Yadlin A, Ross PL, Pappin DJ, Rush J, Lauffenburger DA, White FM | title = Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules | journal = Molecular & Cellular Proteomics | volume = 4 | issue = 9 | pages = 1240–1250 | date = September 2005 | pmid = 15951569 | doi = 10.1074/mcp.M500089-MCP200 | doi-access = free }} * {{cite journal | vauthors = Yoshimoto N, Tatematsu K, Koyanagi T, Okajima T, Tanizawa K, Kuroda S | title = Cytoplasmic tethering of a RING protein RBCK1 by its splice variant lacking the RING domain | journal = Biochemical and Biophysical Research Communications | volume = 335 | issue = 2 | pages = 550–557 | date = September 2005 | pmid = 16083853 | doi = 10.1016/j.bbrc.2005.07.104 }} * {{cite journal | vauthors = Bayle J, Lopez S, Iwaï K, Dubreuil P, De Sepulveda P | title = The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins | journal = FEBS Letters | volume = 580 | issue = 11 | pages = 2609–2614 | date = May 2006 | pmid = 16643902 | doi = 10.1016/j.febslet.2006.03.093 | s2cid = 44648698 | doi-access = free }} * {{cite journal | vauthors = Tian Y, Zhang Y, Zhong B, Wang YY, Diao FC, Wang RP, Zhang M, Chen DY, Zhai ZH, Shu HB | display-authors = 6 | title = RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 23 | pages = 16776–16782 | date = June 2007 | pmid = 17449468 | doi = 10.1074/jbc.M701913200 | doi-access = free }} * {{cite journal | vauthors = Wang K, Kim C, Bradfield J, Guo Y, Toskala E, Otieno FG, Hou C, Thomas K, Cardinale C, Lyon GJ, Golhar R, Hakonarson H | display-authors = 6 | title = Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement | journal = Genome Medicine | volume = 5 | issue = 7 | pages = 67 | year = 2013 | pmid = 23889995 | pmc = 3971341 | doi = 10.1186/gm471 | doi-access = free }} {{refend}} {{PDB Gallery|geneid=10616}}
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