LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation

Abstract

The linear ubiquitin chain assembly complex (LUB AC), consisting of SHA N K-associated RH-domain-interacting protein (SHA R PIN), 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 LUB AC in TLR3 signaling and discover a functional interaction between LUB AC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUB AC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUB AC 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 SHA R PIN-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, LUB AC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.