Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9

Abstract Reactive astrogliosis is a pathological feature of spinal cord injury (SCI). The ubiquitin‐proteasome system plays a crucial role in maintaining protein homeostasis and has been widely studied in neuroscience. Little, however, is known about the underlying function of deubiquitinating enzymes in reactive astrogliosis following SCI. Here, we found that ubiquitin‐specific protease 18 (USP18) was significantly upregulated in astrocytes following scratch injury, and in the injured spinal cord in mice. Knockdown of USP18 in vitro and conditional knockout of USP18 in astrocytes (USP18 CKO) in vivo significantly attenuated reactive astrogliosis. In mice, this led to widespread inflammation and poor functional recovery following SCI. In contrast, overexpression of USP18 in mice injected with adeno‐associated virus (AAV)‐USP18 had beneficial effects following SCI. We showed that USP18 binds, deubiquitinates, and thus, stabilizes SRY‐box transcription factor 9 (SOX9), thereby regulating reactive astrogliosis. We also showed that the Hedgehog (Hh) signaling pathway induces expression of USP18 through Gli2‐mediated transcriptional activation after SCI. Administration of the Hh pathway activator SAG significantly increased reactive astrogliosis, reduced lesion area and promoted functional recovery in mice following SCI. Our results demonstrate that USP18 positively regulates reactive astrogliosis by stabilizing SOX9 and identify USP18 as a promising target for the treatment of SCI.