| Title: |
LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
| Authors: |
Zinngrebe, J; Rieser, E; Taraborrelli, L; Peltzer, N; Hartwig, T; Ren, H; Kovacs, I; Endres, C; Draber, P; Darding, M; von Karstedt, S; Lemke, J; Dome, B; Bergmann, M; Ferguson, BJ; Walczak, H |
| Source: |
Journal of Experimental Medicine , 213 (12) pp. 2671-2689. (2016) |
| Publisher Information: |
ROCKEFELLER UNIV PRESS |
| Publication Year: |
2016 |
| Collection: |
University College London: UCL Discovery |
| Description: |
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/1529764/1/Zinngrebe_LUBAC_deficiency.pdf; https://discovery.ucl.ac.uk/id/eprint/1529764/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/1529764/1/Zinngrebe_LUBAC_deficiency.pdf; https://discovery.ucl.ac.uk/id/eprint/1529764/ |
| Rights: |
open |
| Accession Number: |
edsbas.F592D2D |
| Database: |
BASE |