| 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
|
| Resource |
| Mice |
RBRC01828 |
