--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation.
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.
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.|Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, D-89075 Ulm, Germany.
Julia
J
Zinngrebe
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Eva
E
Rieser
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Lucia
L
Taraborrelli
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Nieves
0000-0002-4134-5852
N
Peltzer
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Torsten
T
Hartwig
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK.
Hongwei
0000-0002-6551-7364
H
Ren
National Korányi Institute of Pulmonology, H-1121 Budapest, Hungary.
Ildikó
0000-0003-0742-8707
I
Kovács
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Cornelia
0000-0002-2027-4389
C
Endres
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Peter
P
Draber
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Maurice
M
Darding
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Silvia
S
von Karstedt
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK.
Johannes
J
Lemke
Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
Balazs
B
Dome
Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
Michael
0000-0001-8529-1166
M
Bergmann
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK.
Brian J
0000-0002-6873-1032
BJ
Ferguson
Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, England, UK h.walczak@ucl.ac.uk.
Henning
H
Walczak
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D003872:Dermatitis / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D053418:Death Domain Receptor Signaling Adaptor Proteins; D009419:Nerve Tissue Proteins; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; C425287:sharpin; C504507:RBCK1 protein, human; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D011070:Poly I-C