The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC

Yasuhiro Fuseya; Hiroaki Fujita; Minsoo Kim; Fumiaki Ohtake; Akira Nishide; Katsuhiro Sasaki; Yasushi Saeki; Keiji Tanaka; Ryosuke Takahashi; Kazuhiro Iwai

doi:10.1038/s41556-020-0517-9

The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC

Nat Cell Biol. 2020 Jun;22(6):663-673. doi: 10.1038/s41556-020-0517-9. Epub 2020 May 11.

Authors

Yasuhiro Fuseya^{1

2}, Hiroaki Fujita¹, Minsoo Kim^{1

3}, Fumiaki Ohtake^{4

5}, Akira Nishide^{1

3}, Katsuhiro Sasaki¹, Yasushi Saeki⁴, Keiji Tanaka⁴, Ryosuke Takahashi², Kazuhiro Iwai⁶

Affiliations

¹ Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Neurology, Graduate School of Medicine, Kyoto University Hospital, Kyoto, Japan.
³ The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan.
⁴ Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
⁵ Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan.
⁶ Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].

PMID: 32393887
DOI: 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Carrier Proteins
HOIL-1L protein, mouse
Intracellular Signaling Peptides and Proteins
NF-kappa B
Sipl1 protein, mouse
Ubiquitin
Rnf31 protein, mouse
Ubiquitin-Protein Ligases