USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2

Abstract

Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin‐specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke‐induced neuronal loss and neurological deficits by inhibiting microglia‐mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF‐κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63‐specific polyubiquitin chains from TAB2. AAV9‐mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke.

Ubiquitous regulation of cerebrovascular diseases by ubiquitin‐modifying enzymes

“…As such, multiple UMEs have been shown to influence ischemic stroke injury by regulating neuroinflammation (Figure 3). Ischemic stroke‐induced neuroinflammation has been shown to be promoted by TRIM8, 71 TRIM45, 72 TRIM47 73 and TRIM62, 74 and inhibited by TRIM9, 13 USP10, 75 USP18, 76 USP20, 77 and USP25 78 . For example, after CI/R injury, microglia‐mediated neuroinflammation and neurological deficit are enhanced by the E3 ligase TRIM45 72 .…”

“…Moreover, microglia‐specific knockdown of TRIM45 significantly mitigates neurological deficit following CI/R injury in mice 72 . In sharp contrast to TRIM45, the DUB USP25 inhibits CI/R‐induced K63 ubiquitination of TAB2 in microglia 78 . In both mice and humans, microglial expression of USP25 is upregulated in the ischemic penumbra 78 .…”

“…USP25 physically interacts with TAB2 through the UIM2 domain and cleaves K63 polyubiquitin chains on TAB2. In mice, ablation of USP25 significantly exacerbated MCAO‐induced cerebral deficits by enhancing neuroinflammation 78 . Ubiquitination and degradation of IκBα, the inhibitor that retains NF‐κB in the cytoplasm in resting cells, is essential for the activation of NF‐κB signaling.…”

“…Ischemic stroke‐induced neuroinflammation has been shown to be promoted by TRIM8, 71 TRIM45, 72 TRIM47 73 and TRIM62, 74 and inhibited by TRIM9, 13 USP10, 75 USP18, 76 USP20, 77 and USP25. 78 For example, after CI/R injury, microglia‐mediated neuroinflammation and neurological deficit are enhanced by the E3 ligase TRIM45. 72 After OGD/R, TRIM45 catalyzes K63‐specific polyubiquitination on TAB2, which is crucial for the phosphorylation of TAK1 and the subsequent activation of NF‐κB signaling.…”

“… 72 In sharp contrast to TRIM45, the DUB USP25 inhibits CI/R‐induced K63 ubiquitination of TAB2 in microglia. 78 In both mice and humans, microglial expression of USP25 is upregulated in the ischemic penumbra. 78 USP25 physically interacts with TAB2 through the UIM2 domain and cleaves K63 polyubiquitin chains on TAB2.…”