Project Summary

The ubiquitin-specific protease 18 (USP18) functions as a major negative regulator of the type I IFN response,
by competing with JAK1 for binding to IFNAR2. USP18 loss-of-function mutations cause hyperactivation
of microglia and result in early-onset childhood interferonopathy. STAT2 and ISG15 are main regulators
of USP18 and, due to impaired USP18-mediated termination of IFN signaling, patients with defects in
these proteins show neurological symptoms reminiscent of the ones caused by USP18 defects. Since
USP18 represents a central gatekeeper of microglia activity, it constitutes an attractive target to modulate
microglia function. In this project, we will define the molecular aspects of how USP18 controls immune homeostasis in specific subsets of CNS myeloid cells both in steady state conditions and upon perturbation by
infection. Focusing on novel interaction partners of USP18 and on the crosstalk between ISG15 with USP18
in a humanized mouse model, we aim to modulate the IFN-dependent activation status of microglia, held in
check by USP18, for therapeutic purposes.