The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC
- 11 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 22 (6), 663-673
- https://doi.org/10.1038/s41556-020-0517-9
Abstract
The linear ubiquitin chain assembly complex (LUBAC), which consists of HOIP, SHARPIN and HOIL-1L, promotes NF-κB activation and protects against cell death by generating linear ubiquitin chains. LUBAC contains two RING-IBR-RING (RBR) ubiquitin ligases (E3), and the HOIP RBR is responsible for catalysing linear ubiquitination. We found that HOIL-1L RBR plays a crucial role in regulating LUBAC. HOIL-1L RBR conjugates monoubiquitin onto all LUBAC subunits, followed by HOIP-mediated conjugation of linear chains onto monoubiquitin, and these linear chains attenuate the functions of LUBAC. The introduction of E3-defective HOIL-1L mutants into cells augmented linear ubiquitination, which protected the cells against Salmonella infection and cured dermatitis caused by reduced LUBAC levels due to SHARPIN loss. Our results reveal a regulatory mode of E3 ligases in which the accessory E3 in LUBAC downregulates the main E3 by providing preferred substrates for autolinear ubiquitination. Thus, inhibition of HOIL-1L E3 represents a promising strategy for treating severe infections or immunodeficiency.Keywords
Funding Information
- MEXT | Japan Society for the Promotion of Science (24112002, 25253019, JP17H06174, JP18H05499, JP17K08786, JP18H05498)
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