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The deubiquitinase OTUD7B ameliorates central nervous system autoimmunity by inhibiting degradation of glial fibrillary acidic protein and astrocyte hyperinflammation

ABSTRACT: Astrocytes are central to the pathogenesis of multiple sclerosis; however, their regulation by intrinsic post-translational ubiquitination and deubiquitination is unresolved. This study shows that the deubiquitinating enzyme OTUD7B in astrocytes confers protection against murine experimental autoimmune encephalomyelitis, a model of MS, by limiting neuroinflammation. RNA-sequencing of isolated astrocytes and spatial transcriptomics showed that in EAE OTUD7B downregulates the expression of chemokines in astrocytes of inflammatory lesions, which is associated with reduced recruitment of encephalitogenic CD4+ T cells. Furthermore, OTUD7B was essential for GFAP protein expression of astrocytes bordering inflammatory lesions. Mechanistically, OTUD7B (i) restricted TNF-induced chemokine production of astrocytes by sequential K63- and K48-deubiquitination of RIPK1 limiting NF-κB and MAPK activation and (ii) enabled GFAP protein expression by supporting GFAP mRNA expression and preventing its proteasomal degradation through K48-deubiquitination of GFAP. This dual action on TNF signaling and GFAP identifies astrocyte-intrinsic OTUD7B as a central inhibitor of astrocyte-mediated inflammation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE286422 | GEO | 2025/08/22

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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The deubiquitinase OTUD7B ameliorates central nervous system autoimmunity by inhibiting degradation of glial fibrillary acidic protein and astrocyte hyperinflammation

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