LUBAC explained

Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex and the only known E3 ubiquitin ligase able to conjugate ubiquitin in a head-to-tail manner to generate linear (M1-linked) polyubiquitin chains. The complex is currently known to be composed of three proteins: heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), HOIL-1-interacting protein (HOIP), and Shank-associated RH domain-interacting protein (SHARPIN)[1] , [2] ,.[3] HOIL-1 and HOIP are both E3 ubiquitin ligases, however, the specific linear ubiquitin-ligating activity is enacted by HOIP.[4] Mice deficient in HOIP are embryonically lethal.[5] Two cases of mutated HOIP have been detected in humans. These patients presented with autoinflammation and immunodeficiency[6] ,.[7] HOIL-1 is required for LUBAC assembly and stability as demonstrated by embryonic lethality in HOIL-1 deficient mice.[8] Recently, it has been noted, that HOIL-1 is also able to catalyze formation of oxyester bonds between the C-terminus of ubiquitin and serine/threonine of substrate protein in TLR signaling.[9] SHARPIN exhibits a significant sequence similarity to HOIL-1 and is important for LUBAC stability. Spontaneous point mutation in the Sharpin gene in mice leads to development of chronic proliferative dermatitis (cpdm)[10] ,.[11] Both HOIL-1 and SHARPIN bind to HOIP through their ubiquitin-like (UBL) domain,. LUBAC consisting of either HOIP-HOIL-1 or HOIP-SHARPIN is functional in vitro, however the greatest activity of the complex has been observed in the presence of all three components.

LUBAC modulates signaling complexes activating the canonical NF-kB pathway in response to various stimuli (e.g., TNF, IL-1, CD40L) by adding M1-linked polyubiquitin chains to signaling proteins,.[12] Additionally, LUBAC has been shown to interact with PKC and NLRP3/ASC inflammasome[13] ,.[14]

Antagonistic to LUBAC are deubiquitinases such as OTULIN or CYLD, of which OTULIN is the only deubiquitinase that removes M1-linked ubiquitin linkages exclusively.[15]

LUBAC components have been most widely studied in the context of TNF signaling.

Notes and References

  1. Kirisako . Takayoshi . Kamei . Kiyoko . Murata . Shigeo . Kato . Michiko . Fukumoto . Hiromi . Kanie . Masato . Sano . Soichi . Tokunaga . Fuminori . Tanaka . Keiji . Iwai . Kazuhiro . 2006-10-18 . A ubiquitin ligase complex assembles linear polyubiquitin chains . The EMBO Journal . 25 . 20 . 4877–4887 . 10.1038/sj.emboj.7601360 . 0261-4189 . 1618115 . 17006537.
  2. Gerlach . Björn . Cordier . Stefanie M. . Schmukle . Anna C. . Emmerich . Christoph H. . Rieser . Eva . Haas . Tobias L. . Webb . Andrew I. . Rickard . James A. . Anderton . Holly . Wong . Wendy W.-L. . Nachbur . Ueli . Gangoda . Lahiru . Warnken . Uwe . Purcell . Anthony W. . Silke . John . March 2011 . Linear ubiquitination prevents inflammation and regulates immune signalling . Nature . en . 471 . 7340 . 591–596 . 10.1038/nature09816 . 21455173 . 4384869 . 1476-4687.
  3. Ikeda . Fumiyo . Deribe . Yonathan Lissanu . Skånland . Sigrid S. . Stieglitz . Benjamin . Grabbe . Caroline . Franz-Wachtel . Mirita . van Wijk . Sjoerd J. L. . Goswami . Panchali . Nagy . Vanja . Terzic . Janos . Tokunaga . Fuminori . Androulidaki . Ariadne . Nakagawa . Tomoko . Pasparakis . Manolis . Iwai . Kazuhiro . March 2011 . SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis . Nature . en . 471 . 7340 . 637–641 . 10.1038/nature09814 . 1476-4687 . 3085511 . 21455181.
  4. Smit . Judith J . Monteferrario . Davide . Noordermeer . Sylvie M . van Dijk . Willem J . van der Reijden . Bert A . Sixma . Titia K . 2012-10-03 . The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension: HOIP RBR-LDD module specifies linear ubiquitin chains . The EMBO Journal . en . 31 . 19 . 3833–3844 . 10.1038/emboj.2012.217 . 3463842 . 22863777.
  5. Peltzer . Nieves . Rieser . Eva . Taraborrelli . Lucia . Draber . Peter . Darding . Maurice . Pernaute . Barbara . Shimizu . Yutaka . Sarr . Aida . Draberova . Helena . Montinaro . Antonella . Martinez-Barbera . Juan Pedro . Silke . John . Rodriguez . Tristan A. . Walczak . Henning . 2014-10-09 . HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death . Cell Reports . English . 9 . 1 . 153–165 . 10.1016/j.celrep.2014.08.066 . 2211-1247 . 25284787. free .
  6. Boisson . Bertrand . Laplantine . Emmanuel . Dobbs . Kerry . Cobat . Aurélie . Tarantino . Nadine . Hazen . Melissa . Lidov . Hart G.W. . Hopkins . Gregory . Du . Likun . Belkadi . Aziz . Chrabieh . Maya . Itan . Yuval . Picard . Capucine . Fournet . Jean-Christophe . Eibel . Hermann . 2015-06-01 . Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia . Journal of Experimental Medicine . en . 212 . 6 . 939–951 . 10.1084/jem.20141130 . 1540-9538 . 4451137 . 26008899.
  7. Oda . Hirotsugu . Beck . David B. . Kuehn . Hye Sun . Sampaio Moura . Natalia . Hoffmann . Patrycja . Ibarra . Maria . Stoddard . Jennifer . Tsai . Wanxia Li . Gutierrez-Cruz . Gustavo . Gadina . Massimo . Rosenzweig . Sergio D. . Kastner . Daniel L. . Notarangelo . Luigi D. . Aksentijevich . Ivona . 2019-03-18 . Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC . Frontiers in Immunology . 10 . 479 . 10.3389/fimmu.2019.00479 . 1664-3224 . 6431612 . 30936877 . free .
  8. Peltzer . Nieves . Darding . Maurice . Montinaro . Antonella . Draber . Peter . Draberova . Helena . Kupka . Sebastian . Rieser . Eva . Fisher . Amanda . Hutchinson . Ciaran . Taraborrelli . Lucia . Hartwig . Torsten . Lafont . Elodie . Haas . Tobias L. . Shimizu . Yutaka . Böiers . Charlotta . May 2018 . LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis . Nature . en . 557 . 7703 . 112–117 . 10.1038/s41586-018-0064-8 . 1476-4687 . 5947819 . 29695863.
  9. Kelsall . Ian R. . Zhang . Jiazhen . Knebel . Axel . Arthur . J. Simon C. . Cohen . Philip . 2019-07-02 . The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells . Proceedings of the National Academy of Sciences . en . 116 . 27 . 13293–13298 . 10.1073/pnas.1905873116 . 0027-8424 . 6613137 . 31209050 . free .
  10. HogenEsch . H. . Torregrosa . S. E. . Boggess . D. . Sundberg . B. A. . Carroll . J. . Sundberg . J. P. . March 2001 . Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12 . European Journal of Immunology . 31 . 3 . 734–742 . 10.1002/1521-4141(200103)31:3<734::aid-immu734>3.0.co;2-9 . 0014-2980 . 11241277. 9944119 .
  11. Seymour . R E . Hasham . M G . Cox . G A . Shultz . L D . HogenEsch . H . Roopenian . D C . Sundberg . J P . July 2007 . Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis . Genes & Immunity . en . 8 . 5 . 416–421 . 10.1038/sj.gene.6364403 . 17538631 . 27135591 . 1466-4879.
  12. Tokunaga . Fuminori . Sakata . Shin-ichi . Saeki . Yasushi . Satomi . Yoshinori . Kirisako . Takayoshi . Kamei . Kiyoko . Nakagawa . Tomoko . Kato . Michiko . Murata . Shigeo . Yamaoka . Shoji . Yamamoto . Masahiro . Akira . Shizuo . Takao . Toshifumi . Tanaka . Keiji . Iwai . Kazuhiro . February 2009 . Involvement of linear polyubiquitylation of NEMO in NF-κB activation . Nature Cell Biology . en . 11 . 2 . 123–132 . 10.1038/ncb1821 . 19136968 . 23733705 . 1465-7392.
  13. Rodgers . Mary A. . Bowman . James W. . Fujita . Hiroaki . Orazio . Nicole . Shi . Mude . Liang . Qiming . Amatya . Rina . Kelly . Thomas J. . Iwai . Kazuhiro . Ting . Jenny . Jung . Jae U. . 2014-06-30 . The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation . Journal of Experimental Medicine . en . 211 . 7 . 1333–1347 . 10.1084/jem.20132486 . 1540-9538 . 4076580 . 24958845.
  14. Nakamura . Munehiro . Tokunaga . Fuminori . Sakata . Shin-ichi . Iwai . Kazuhiro . December 2006 . Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex . Biochemical and Biophysical Research Communications . en . 351 . 2 . 340–347 . 10.1016/j.bbrc.2006.09.163. 17069764 .
  15. Keusekotten . Kirstin . Elliott . Paul Ronald . Glockner . Laura . Fiil . Berthe Katrine . Damgaard . Rune Busk . Kulathu . Yogesh . Wauer . Tobias . Hospenthal . Manuela Kathrin . Gyrd-Hansen . Mads . Krappmann . Daniel . Hofmann . Kay . Komander . David . June 2013 . OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin . Cell . en . 153 . 6 . 1312–1326 . 10.1016/j.cell.2013.05.014 . 3690481 . 23746843.

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