USP18 as an immune checkpoint regulator for microglia activation

PD Dr. Klaus-Peter Knobeloch

• B16

Prof. Dr. Antje Beling

• B16

Project Summary

Type I Interferons (IFN) play a central role in the innate immune response. Ubiquiti n-specific protease (USP) 18 in concert with ISG15 and STAT2 acts as a main gatekeeper to terminate IFN signaling and to prevent aberrant microglia (MG) activation. Consequently, mice or patients lacking USP18 develop fatal interferonopathies and microgliosis. Only in humans but not in mice, ISG15 exerts a stabilizing effect on USP18 unveiling fundamental species-specific differences in the USP18 signaling hub. By replacing murine with human Usp18 (Usp18^{hUSP18/hUSP18} mice), we found that human USP18 cannot restore tonic IFN-signaling, embryonic lethality or hydrocephalus formati on and microgliosis in surviving adult mice. We will closely investigate the function of USP18 for brain integrity and MG development and study the effects of a recently published role of USP18 in securing colony stimulating factor (CSF) 1 receptor stability (Aim1).
To explore modifier effects, we will profile Usp18^hUSP18 mice with different genetic backgrounds (Aim2) affecting the phenotypic outcome. To study species–specific propertes and to pave the road for intervention strategies in humans, we will develop a humanized mouse model (Usp18^hUSP18:Isg15^hISG15:Stat2^hSTAT2) for the USP18 signaling hub (Aim 3). We will investi gate how USP18 controls microgliosis and brain inflammation once tonic IFN signaling is overcome, e.g. by viral infection or TLR ligands, both potent activators of microglia (Aim 4). Synergistically, we aim for systemic resolution of USP18 guidance of MG bioenergetics under homeostatic and virus-activated conditions. Preliminary data point to a gate keeper function of USP18 in the control of glycolysis and its coupling to downstream oxidative pathways. We will profi le the MG proteome, metabolome and mitochondrial metabolic capacity, complemented by functional studies and proteomics-based computational modeling of metabolism in homeostatic, TLR-IFN and RNA virus-induced proinflammatory conditions (Aim 5).