Abstract
Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation.
Highlights
Autoinflammatory diseases are a diverse group of inherited conditions characterized by early-onset systemic inflammation and are accompanied by a range of organ-specific manifestations
linear ubiquitin chain assembly complex (LUBAC) depletion leads to attenuation of NF-kB and the mitogen-activated protein kinases (MAPK)-mediated signaling and increases cell death
Inherited loss-of-function mutations in the linear (Met1)-specific DUB OTULIN have been linked to the earlyonset severe inflammatory disease, named otulipenia/otulin-related autoinflammatory syndrome (ORAS) (Table 1) [17, 18]
Summary
Autoinflammatory diseases are a diverse group of inherited conditions characterized by early-onset systemic inflammation and are accompanied by a range of organ-specific manifestations. The ubiquitination process is initiated by the attachment of a single Ub molecule to a target protein through a three-step enzymatic pathway that includes Ub-activating enzymes (E1), Ub-conjugating enzymes (E2), and Ub-ligating enzymes (E3) [2]. This review will primarily focus on two diseases caused by malfunction in DUB enzymes, TNFAIP3/ A20 and OTULIN, which are known to hydrolyze Lys63- and Met1-linked Ub chains, respectively. In both conditions, HA20 and otulipenia/ORAS, a defect in DUB activity results in excessive ubiquitination and increased activity of key signaling molecules in the canonical NF-kB pathway. LUBAC-associated diseases will be briefly discussed in the context of LUBAC–OTULIN interactions
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