LUBAC

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){{Cite journal |last1=Kirisako |first1=Takayoshi |last2=Kamei |first2=Kiyoko |last3=Murata |first3=Shigeo |last4=Kato |first4=Michiko |last5=Fukumoto |first5=Hiromi |last6=Kanie |first6=Masato |last7=Sano |first7=Soichi |last8=Tokunaga |first8=Fuminori |last9=Tanaka |first9=Keiji |last10=Iwai |first10=Kazuhiro |date=2006-10-18 |title=A ubiquitin ligase complex assembles linear polyubiquitin chains |journal=The EMBO Journal |volume=25 |issue=20 |pages=4877–4887 |doi=10.1038/sj.emboj.7601360 |issn=0261-4189 |pmc=1618115 |pmid=17006537}}^, {{Cite journal |last1=Gerlach |first1=Björn |last2=Cordier |first2=Stefanie M. |last3=Schmukle |first3=Anna C. |last4=Emmerich |first4=Christoph H. |last5=Rieser |first5=Eva |last6=Haas |first6=Tobias L. |last7=Webb |first7=Andrew I. |last8=Rickard |first8=James A. |last9=Anderton |first9=Holly |last10=Wong |first10=Wendy W.-L. |last11=Nachbur |first11=Ueli |last12=Gangoda |first12=Lahiru |last13=Warnken |first13=Uwe |last14=Purcell |first14=Anthony W. |last15=Silke |first15=John |date=March 2011 |title=Linear ubiquitination prevents inflammation and regulates immune signalling |url=https://www.nature.com/articles/nature09816 |journal=Nature |language=en |volume=471 |issue=7340 |pages=591–596 |doi=10.1038/nature09816 |pmid=21455173 |s2cid=4384869 |issn=1476-4687|url-access=subscription }}^,.{{Cite journal |last1=Ikeda |first1=Fumiyo |last2=Deribe |first2=Yonathan Lissanu |last3=Skånland |first3=Sigrid S. |last4=Stieglitz |first4=Benjamin |last5=Grabbe |first5=Caroline |last6=Franz-Wachtel |first6=Mirita |last7=van Wijk |first7=Sjoerd J. L. |last8=Goswami |first8=Panchali |last9=Nagy |first9=Vanja |last10=Terzic |first10=Janos |last11=Tokunaga |first11=Fuminori |last12=Androulidaki |first12=Ariadne |last13=Nakagawa |first13=Tomoko |last14=Pasparakis |first14=Manolis |last15=Iwai |first15=Kazuhiro |date=March 2011 |title=SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis |journal=Nature |language=en |volume=471 |issue=7340 |pages=637–641 |doi=10.1038/nature09814 |issn=1476-4687 |pmc=3085511 |pmid=21455181}} HOIL-1 and HOIP are both E3 ubiquitin ligases, however, the specific linear ubiquitin-ligating activity is enacted by HOIP.{{Cite journal |last1=Smit |first1=Judith J |last2=Monteferrario |first2=Davide |last3=Noordermeer |first3=Sylvie M |last4=van Dijk |first4=Willem J |last5=van der Reijden |first5=Bert A |last6=Sixma |first6=Titia K |date=2012-10-03 |title=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 |journal=The EMBO Journal |language=en |volume=31 |issue=19 |pages=3833–3844 |doi=10.1038/emboj.2012.217 |pmc=3463842 |pmid=22863777}} Mice deficient in HOIP are embryonically lethal.{{Cite journal |last1=Peltzer |first1=Nieves |last2=Rieser |first2=Eva |last3=Taraborrelli |first3=Lucia |last4=Draber |first4=Peter |last5=Darding |first5=Maurice |last6=Pernaute |first6=Barbara |last7=Shimizu |first7=Yutaka |last8=Sarr |first8=Aida |last9=Draberova |first9=Helena |last10=Montinaro |first10=Antonella |last11=Martinez-Barbera |first11=Juan Pedro |last12=Silke |first12=John |last13=Rodriguez |first13=Tristan A. |last14=Walczak |first14=Henning |date=2014-10-09 |title=HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death |url=https://www.cell.com/cell-reports/abstract/S2211-1247(14)00742-6 |journal=Cell Reports |language=English |volume=9 |issue=1 |pages=153–165 |doi=10.1016/j.celrep.2014.08.066 |issn=2211-1247 |pmid=25284787|doi-access=free }} Two cases of mutated HOIP have been detected in humans. These patients presented with autoinflammation and immunodeficiency{{Cite journal |last1=Boisson |first1=Bertrand |last2=Laplantine |first2=Emmanuel |last3=Dobbs |first3=Kerry |last4=Cobat |first4=Aurélie |last5=Tarantino |first5=Nadine |last6=Hazen |first6=Melissa |last7=Lidov |first7=Hart G.W. |last8=Hopkins |first8=Gregory |last9=Du |first9=Likun |last10=Belkadi |first10=Aziz |last11=Chrabieh |first11=Maya |last12=Itan |first12=Yuval |last13=Picard |first13=Capucine |last14=Fournet |first14=Jean-Christophe |last15=Eibel |first15=Hermann |date=2015-06-01 |title=Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia |url=https://rupress.org/jem/article/212/6/939/41820/Human-HOIP-and-LUBAC-deficiency-underlies |journal=Journal of Experimental Medicine |language=en |volume=212 |issue=6 |pages=939–951 |doi=10.1084/jem.20141130 |issn=1540-9538 |pmc=4451137 |pmid=26008899}}^,.{{Cite journal |last1=Oda |first1=Hirotsugu |last2=Beck |first2=David B. |last3=Kuehn |first3=Hye Sun |last4=Sampaio Moura |first4=Natalia |last5=Hoffmann |first5=Patrycja |last6=Ibarra |first6=Maria |last7=Stoddard |first7=Jennifer |last8=Tsai |first8=Wanxia Li |last9=Gutierrez-Cruz |first9=Gustavo |last10=Gadina |first10=Massimo |last11=Rosenzweig |first11=Sergio D. |last12=Kastner |first12=Daniel L. |last13=Notarangelo |first13=Luigi D. |last14=Aksentijevich |first14=Ivona |date=2019-03-18 |title=Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC |journal=Frontiers in Immunology |volume=10 |pages=479 |doi=10.3389/fimmu.2019.00479 |issn=1664-3224 |pmc=6431612 |pmid=30936877 |doi-access=free }} HOIL-1 is required for LUBAC assembly and stability as demonstrated by embryonic lethality in HOIL-1 deficient mice.{{Cite journal |last1=Peltzer |first1=Nieves |last2=Darding |first2=Maurice |last3=Montinaro |first3=Antonella |last4=Draber |first4=Peter |last5=Draberova |first5=Helena |last6=Kupka |first6=Sebastian |last7=Rieser |first7=Eva |last8=Fisher |first8=Amanda |last9=Hutchinson |first9=Ciaran |last10=Taraborrelli |first10=Lucia |last11=Hartwig |first11=Torsten |last12=Lafont |first12=Elodie |last13=Haas |first13=Tobias L. |last14=Shimizu |first14=Yutaka |last15=Böiers |first15=Charlotta |date=May 2018 |title=LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis |journal=Nature |language=en |volume=557 |issue=7703 |pages=112–117 |doi=10.1038/s41586-018-0064-8 |issn=1476-4687 |pmc=5947819 |pmid=29695863}} 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.{{Cite journal |last1=Kelsall |first1=Ian R. |last2=Zhang |first2=Jiazhen |last3=Knebel |first3=Axel |last4=Arthur |first4=J. Simon C. |last5=Cohen |first5=Philip |date=2019-07-02 |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 |language=en |volume=116 |issue=27 |pages=13293–13298 |doi=10.1073/pnas.1905873116 |issn=0027-8424 |pmc=6613137 |pmid=31209050 |doi-access=free }} 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){{Cite journal |last1=HogenEsch |first1=H. |last2=Torregrosa |first2=S. E. |last3=Boggess |first3=D. |last4=Sundberg |first4=B. A. |last5=Carroll |first5=J. |last6=Sundberg |first6=J. P. |date=March 2001 |title=Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12 |url=https://pubmed.ncbi.nlm.nih.gov/11241277 |journal=European Journal of Immunology |volume=31 |issue=3 |pages=734–742 |doi=10.1002/1521-4141(200103)31:3<734::aid-immu734>3.0.co;2-9 |issn=0014-2980 |pmid=11241277|s2cid=9944119 }}^,.{{Cite journal |last1=Seymour |first1=R E |last2=Hasham |first2=M G |last3=Cox |first3=G A |last4=Shultz |first4=L D |last5=HogenEsch |first5=H |last6=Roopenian |first6=D C |last7=Sundberg |first7=J P |date=July 2007 |title=Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis |url=https://www.nature.com/articles/6364403 |journal=Genes & Immunity |language=en |volume=8 |issue=5 |pages=416–421 |doi=10.1038/sj.gene.6364403 |pmid=17538631 |s2cid=27135591 |issn=1466-4879|url-access=subscription }} 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^,.{{Cite journal |last1=Tokunaga |first1=Fuminori |last2=Sakata |first2=Shin-ichi |last3=Saeki |first3=Yasushi |last4=Satomi |first4=Yoshinori |last5=Kirisako |first5=Takayoshi |last6=Kamei |first6=Kiyoko |last7=Nakagawa |first7=Tomoko |last8=Kato |first8=Michiko |last9=Murata |first9=Shigeo |last10=Yamaoka |first10=Shoji |last11=Yamamoto |first11=Masahiro |last12=Akira |first12=Shizuo |last13=Takao |first13=Toshifumi |last14=Tanaka |first14=Keiji |last15=Iwai |first15=Kazuhiro |date=February 2009 |title=Involvement of linear polyubiquitylation of NEMO in NF-κB activation |url=http://www.nature.com/articles/ncb1821 |journal=Nature Cell Biology |language=en |volume=11 |issue=2 |pages=123–132 |doi=10.1038/ncb1821 |pmid=19136968 |s2cid=23733705 |issn=1465-7392|url-access=subscription }} Additionally, LUBAC has been shown to interact with PKC and NLRP3/ASC inflammasome{{Cite journal |last1=Rodgers |first1=Mary A. |last2=Bowman |first2=James W. |last3=Fujita |first3=Hiroaki |last4=Orazio |first4=Nicole |last5=Shi |first5=Mude |last6=Liang |first6=Qiming |last7=Amatya |first7=Rina |last8=Kelly |first8=Thomas J. |last9=Iwai |first9=Kazuhiro |last10=Ting |first10=Jenny |last11=Jung |first11=Jae U. |date=2014-06-30 |title=The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation |url=https://rupress.org/jem/article/211/7/1333/41630/The-linear-ubiquitin-assembly-complex-LUBAC-is |journal=Journal of Experimental Medicine |language=en |volume=211 |issue=7 |pages=1333–1347 |doi=10.1084/jem.20132486 |issn=1540-9538 |pmc=4076580 |pmid=24958845}}^,.{{Cite journal |last1=Nakamura |first1=Munehiro |last2=Tokunaga |first2=Fuminori |last3=Sakata |first3=Shin-ichi |last4=Iwai |first4=Kazuhiro |date=December 2006 |title=Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex |url=https://linkinghub.elsevier.com/retrieve/pii/S0006291X06022236 |journal=Biochemical and Biophysical Research Communications |language=en |volume=351 |issue=2 |pages=340–347 |doi=10.1016/j.bbrc.2006.09.163|pmid=17069764 |url-access=subscription }}

Antagonistic to LUBAC are deubiquitinases such as OTULIN or CYLD, of which OTULIN is the only deubiquitinase that removes M1-linked ubiquitin linkages exclusively.{{Cite journal |last1=Keusekotten |first1=Kirstin |last2=Elliott |first2=Paul Ronald |last3=Glockner |first3=Laura |last4=Fiil |first4=Berthe Katrine |last5=Damgaard |first5=Rune Busk |last6=Kulathu |first6=Yogesh |last7=Wauer |first7=Tobias |last8=Hospenthal |first8=Manuela Kathrin |last9=Gyrd-Hansen |first9=Mads |last10=Krappmann |first10=Daniel |last11=Hofmann |first11=Kay |last12=Komander |first12=David |date=June 2013 |title=OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin |journal=Cell |language=en |volume=153 |issue=6 |pages=1312–1326 |doi=10.1016/j.cell.2013.05.014 |pmc=3690481 |pmid=23746843}}

LUBAC components have been most widely studied in the context of TNF signaling.{{cn|date=June 2023}}