RRC ID 80701
Author Fuseya Y, Fujita H, Kim M, Ohtake F, Nishide A, Sasaki K, Saeki Y, Tanaka K, Takahashi R, Iwai K.
Title The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC.
Journal Nat Cell Biol
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.
Volume 22(6)
Pages 663-673
Published 2020-6-1
DOI 10.1038/s41556-020-0517-9
PII 10.1038/s41556-020-0517-9
PMID 32393887
MeSH Animals Carrier Proteins / physiology* Cell Death* Cells, Cultured Chemical and Drug Induced Liver Injury / immunology* Chemical and Drug Induced Liver Injury / metabolism Chemical and Drug Induced Liver Injury / pathology Dermatitis, Contact / immunology* Dermatitis, Contact / metabolism Dermatitis, Contact / pathology Embryo, Mammalian / immunology Embryo, Mammalian / metabolism Embryo, Mammalian / pathology Fibroblasts / immunology Fibroblasts / metabolism Fibroblasts / pathology Gene Expression Regulation Intracellular Signaling Peptides and Proteins / physiology* Mice, Knockout NF-kappa B / genetics NF-kappa B / metabolism Salmonella / pathogenicity Salmonella Infections, Animal / immunology* Salmonella Infections, Animal / metabolism Salmonella Infections, Animal / pathology Severity of Illness Index Signal Transduction Ubiquitin / metabolism* Ubiquitin-Protein Ligases / physiology* Ubiquitination
Mice RBRC01828