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A partial form of inherited human USP18 deficiency underlies infection and inflammation

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.
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Contributor : Françoise Vuillier Connect in order to contact the contributor
Submitted on : Wednesday, June 1, 2022 - 2:54:56 PM
Last modification on : Thursday, October 20, 2022 - 3:10:07 PM
Long-term archiving on: : Friday, September 2, 2022 - 7:23:23 PM


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Marta Martin-Fernandez, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, et al.. A partial form of inherited human USP18 deficiency underlies infection and inflammation. Journal of Experimental Medicine, 2022, 219 (4), ⟨10.1084/jem.20211273⟩. ⟨pasteur-03684590⟩



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