| First Author | Gomez-Diaz C | Year | 2021 |
| Journal | iScience | Volume | 24 |
| Issue | 11 | Pages | 103241 |
| PubMed ID | 34755089 | Mgi Jnum | J:319466 |
| Mgi Id | MGI:6828914 | Doi | 10.1016/j.isci.2021.103241 |
| Citation | Gomez-Diaz C, et al. (2021) The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains. iScience 24(11):103241 |
| abstractText | The Linear Ubiquitin Chain Assembly Complex (LUBAC), composed of HOIP, HOIL-1L, and SHARPIN, promotes tumor necrosis factor (TNF)-dependent NF-kappaB 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-kappaB 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. |
