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

Gomez Diaz, C.; Jonsson, G.; Schodl, K.; Deszcz, L.; Bestehorn, A.; Eislmayr, K.; Almagro, J.; Kavirayani, A.; Fennell, L. M.; Hagelkrueys, A.; Kovarik, P.; Penninger, J. M.; Ikeda, F.

doi:10.1101/2021.04.13.439587

bioRxiv · 10.1101/2021.04.13.439587

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

Gomez Diaz, C.·Jonsson, G.·Schodl, K.·Deszcz, L.·Bestehorn, A.·Eislmayr, K.·Almagro, J.·Kavirayani, A.·Fennell, L. M.·Hagelkrueys, A.·Kovarik, P.·Penninger, J. M.·Ikeda, F.

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Abstract

The Linear Ubiquitin Assembly Complex (LUBAC), composed of HOIP, HOIL-1L and SHARPIN, promotes Tumor Necrosis Factor (TNF)-dependent NF-{kappa}B 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-1lT20;A;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 the HOIL-1L knockin mice show reduced TNF-dependent NF-{kappa}B activation and incomplete recruitment of HOIL-1L into TNF Receptor (TNFR) Complex I. We further show that the HOIL-1L-NZF domain 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.

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Gomez Diaz, C., Jonsson, G., Schodl, K., Deszcz, L., Bestehorn, A., Eislmayr, K., Almagro, J., Kavirayani, A., Fennell, L. M., Hagelkrueys, A., Kovarik, P., Penninger, J. M., Ikeda, F.. 2021-04-13. The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains. https://doi.org/10.1101/2021.04.13.439587

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