The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains
| Autor: | Katrin Schodl, Annika Bestehorn, Pavel Kovarik, Luiza Deszcz, Gustav Jonsson, Astrid Hagelkruys, Jorge Almagro, Kevin Eislmayr, Fumiyo Ikeda, Anoop Kavirayani, Lilian M. Fennell, Carlos Gomez-Diaz, Josef M. Penninger, Mayu Seida |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Zinc finger
Cell type Multidisciplinary biology Chemistry Molecular biology Science medicine.medical_treatment Inflammation Article Ubiquitin ligase Cell biology Biological sciences Immune system Cytokine Ubiquitin biology.protein medicine Tumor necrosis factor alpha medicine.symptom Immune response |
| Zdroj: | iScience iScience, Vol 24, Iss 11, Pp 103241-(2021) |
| DOI: | 10.1016/j.isci.2021.103241 |
| Popis: | 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-1lT201A;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-1lT201A;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 • An RBR-type E3 ligase HOIL-1L decodes linear ubiquitin chains via the NZF domain • HOIL-1L NZF is essential for proper responses to LPS and TNF-induced shock in mice • Intact HOIL-1L NZF is required for activating the TNF-induced NF-kB pathway • HOIL-1L NZF cooperates with SHARPIN to control inflammation in mice Biological sciences; Molecular biology; Immune response |
| Databáze: | OpenAIRE |
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