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[1],.[2] 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.[2]

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[2],.[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.

References

  1. 1 2 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. doi:10.1038/sj.emboj.7601360. ISSN 0261-4189. PMC 1618115. PMID 17006537.
  2. 1 2 3 4 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. 471 (7340): 591–596. doi:10.1038/nature09816. ISSN 1476-4687. PMID 21455173. S2CID 4384869.
  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. 471 (7340): 637–641. doi:10.1038/nature09814. ISSN 1476-4687. PMC 3085511. PMID 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. 31 (19): 3833–3844. doi:10.1038/emboj.2012.217. PMC 3463842. PMID 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. 9 (1): 153–165. doi:10.1016/j.celrep.2014.08.066. ISSN 2211-1247. PMID 25284787.
  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. 212 (6): 939–951. doi:10.1084/jem.20141130. ISSN 1540-9538. PMC 4451137. PMID 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. doi:10.3389/fimmu.2019.00479. ISSN 1664-3224. PMC 6431612. PMID 30936877.
  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. 557 (7703): 112–117. doi:10.1038/s41586-018-0064-8. ISSN 1476-4687. PMC 5947819. PMID 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. 116 (27): 13293–13298. doi:10.1073/pnas.1905873116. ISSN 0027-8424. PMC 6613137. PMID 31209050.
  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. doi:10.1002/1521-4141(200103)31:3<734::aid-immu734>3.0.co;2-9. ISSN 0014-2980. PMID 11241277. S2CID 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. 8 (5): 416–421. doi:10.1038/sj.gene.6364403. ISSN 1466-4879. PMID 17538631. S2CID 27135591.
  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. 11 (2): 123–132. doi:10.1038/ncb1821. ISSN 1465-7392. PMID 19136968. S2CID 23733705.
  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. 211 (7): 1333–1347. doi:10.1084/jem.20132486. ISSN 1540-9538. PMC 4076580. PMID 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. 351 (2): 340–347. doi:10.1016/j.bbrc.2006.09.163. PMID 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. 153 (6): 1312–1326. doi:10.1016/j.cell.2013.05.014. PMC 3690481. PMID 23746843.
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