The HOIL-1L Ligase Modulates Immune Signalling and Cell Death Via Monoubiquitination of LUBAC

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2020 May 13

PMID 32393887

Citations 49

Authors

Yasuhiro Fuseya

Hiroaki Fujita

Minsoo Kim

Fumiaki Ohtake

Akira Nishide

Katsuhiro Sasaki

Yasushi Saeki

Keiji Tanaka

Ryosuke Takahashi

Kazuhiro Iwai

Affiliations

Soon will be listed here.

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.

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