The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains

Summary

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 in vivo 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 ( Hoil-1l ^{T201A;R208A/T201A;R208A} ) 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 Hoil-1l ^{T201A;R208A/T201A;R208A} 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 in vivo.

Graphical abstract

Highlights

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  An RBR-type E3 ligase HOIL-1L decodes linear ubiquitin chains via the NZF domain

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  HOIL-1L NZF is essential for proper responses to LPS and TNF-induced shock in mice

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  Intact HOIL-1L NZF is required for activating the TNF-induced NF-kB pathway

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  HOIL-1L NZF cooperates with SHARPIN to control inflammation in mice

Abstract

Biological sciences; Molecular biology; Immune response