A partial form of inherited human USP18 deficiency underlies infection and inflammation
Marta Martín-Fernández, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, Françoise Vuillier, Lina Franklin, Fatima Ailal, Alice Muglia Thomaz da Silva Amancio, Louise Malle, Conor Gruber, Ibtihal Benhsaien, Jennie Altman, Justin Taft, Caroline Deswarte, Manon Roynard, Alejandro Nieto-Patlán, Kunihiko Moriya, Jérémie Rosain, Nathalie Boddaert, Aziz Bousfiha, Yanick J. Crow, Dragana Janković, Alan Sher, Jean‐Laurent Casanova, Sandra Pellegrini, Jacinta Bustamante, Dusan Bogunovic
Abstract
Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I-mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ-dependent induction of IL-12 and IL-23 is reduced owing to IFN-I-mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.