OTULIN deficiency causes auto-inflammatory syndrome

Abstract

Ubiquitin chains assembled via the N-terminal methionine (Met1 or linear ubiquitin), conjugated by the linear ubiquitin chain assembly complex (LUBAC), participate in NF-κΒ-dependent inflammatory signaling and immune responses. A recent report in Cell finds that OTULIN, a deubiquitinase that selectively cleaves Met1-linked ubiquitin chains, is essential for restraining inflammation in vivo.

Figure 1

Activation of immune receptors triggers assembly of Met1-Ub by LUBAC that facilitates inflammation and under normal conditions is counter-balanced by the DUB OTULIN. Individuals with a loss-of-function mutation in OTULIN (L272P) or mice where OTULIN is deleted in myeloid cells accumulate Met1-Ub, possibly independently of receptor activation, and develop a severe autoinflammatory condition termed ORAS. Significantly, ORAS can be alleviated by the inhibition of TNF.