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)[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

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  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.
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  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.
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