# LUBAC

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**Linear ubiquitin chain assembly complex** (**LUBAC**) is a multi-protein complex and the only known [E3 ubiquitin ligase](/source/E3_Ubiquitin_Ligase) able to conjugate ubiquitin in a head-to-tail manner to generate linear (M1-linked) [polyubiquitin](/source/Polyubiquitination) 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](/source/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](/source/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](/source/Point_mutation) in the *Sharpin* [gene](/source/Gene) in mice leads to development of chronic proliferative [dermatitis](/source/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](/source/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.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

## References

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Adapted from the Wikipedia article [LUBAC](https://en.wikipedia.org/wiki/LUBAC) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/LUBAC?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.