The Ubiquitin Ligase HOIL-1L Regulates Immune Responses by Interacting with Linear Ubiquitin Chains

Overview

Journal iScience

Publisher Cell Press

Date 2021 Nov 10

PMID 34755089

Citations 4

Authors

Carlos Gomez-Diaz

Gustav Jonsson

Katrin Schodl

Luiza Deszcz

Annika Bestehorn

Kevin Eislmayr

Jorge Almagro

Anoop Kavirayani

Mayu Seida

Lilian M Fennell

Astrid Hagelkruys

Pavel Kovarik

Josef M Penninger

Fumiyo Ikeda

Affiliations

Soon will be listed here.

Abstract

The Linear Ubiquitin Chain Assembly Complex (LUBAC), composed of HOIP, HOIL-1L, and SHARPIN, promotes tumor necrosis factor (TNF)-dependent NF-κB signaling in diverse cell types. HOIL-1L contains an Npl4 Zinc Finger (NZF) domain that specifically recognizes linear ubiquitin chains, but its physiological role has remained unclear. Here, we demonstrate that the HOIL-1L NZF domain has important regulatory functions in inflammation and immune responses in mice. We generated knockin mice ( ) expressing a HOIL-1L NZF mutant and observed attenuated responses to TNF- and LPS-induced shock, including prolonged survival, stabilized body temperature, reduced cytokine production, and liver damage markers. Cells derived from mice show reduced TNF-dependent NF-κB activation and incomplete recruitment of HOIL-1L into TNF Receptor (TNFR) Complex I. We further show that HOIL-1L NZF cooperates with SHARPIN to prevent TNFR-dependent skin inflammation. Collectively, our data suggest that linear ubiquitin-chain binding by HOIL-1L regulates immune responses and inflammation .

Citing Articles

Synergistic involvement of the NZF domains of the LUBAC accessory subunits HOIL-1L and SHARPIN in the regulation of LUBAC function.

Toda Y, Fujita H, Mino K, Koyama T, Matsuoka S, Kaizuka T Cell Death Dis. 2024; 15(11):813.

PMID: 39528476 PMC: 11555115. DOI: 10.1038/s41419-024-07199-z.

Mechanistic insights into the enzymatic activity of E3 ligase HOIL-1L and its regulation by the linear ubiquitin chain binding.

Xu X, Wang Y, Zhang Y, Wang Y, Yin Y, Peng C Sci Adv. 2023; 9(41):eadi4599.

PMID: 37831767 PMC: 10575588. DOI: 10.1126/sciadv.adi4599.

Advances in the Structural and Physiological Functions of SHARPIN.

Yu B, Wang F, Wang Y Front Immunol. 2022; 13:858505.

PMID: 35547743 PMC: 9084887. DOI: 10.3389/fimmu.2022.858505.

HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation.

Kelsall I, McCrory E, Xu Y, Scudamore C, Nanda S, Mancebo-Gamella P EMBO J. 2022; 41(8):e109700.

PMID: 35274759 PMC: 9016349. DOI: 10.15252/embj.2021109700.

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