USP18 lack in microglia causes destructive interferonopathy of the mouse brain
20.04.2015
Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L, Basters A, Staszewski O, Brendecke SM, Spiess A, Tay TL, Kreutz C, Timmer J, Mancini GM, Blank T, Fritz G, Biber K, Lang R, Malo D, Merkler D, Heikenwälder M, Knobeloch KP, Prinz M.
EMBO J. 2015;34(12):1612-29.
Microglia are tissue macrophages of the central nervous system(CNS) that control tissue homeostasis. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitinspecific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under nondiseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway.
