An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.
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ABSTRACT:
SUBMITTER: Kim AS
PROVIDER: S-EPMC7163869 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong (ONNV) viruses. To determine its role in pathogenesis, we generated mice with mutant Mxra8 alleles: an 8-nucleotide deletion that produces a truncated, soluble form (Mxra8Δ8/Δ8) and a 97-nucleotide deletion that abolishes Mxra8 expression (Mxra8Δ97/Δ97). Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 fibroblasts show reduced CHIKV infection in culture, and Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 mice have decreased infection of musculoskeletal tissues with CHIKV, MAYV, RRV, or ONNV. Less foot swelling is observed in CHIKV-infected Mxra8 mutant mice, which correlated with fewer infiltrating neutrophils and cytokines. A recombinant E2-D71A CHIKV with diminished binding to Mxra8 is attenuated in vivo in wild-type mice. Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. These studies establish a role for Mxra8 in the pathogenesis of multiple alphaviruses and suggest that targeting this protein may mitigate disease in humans.
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Project description:BackgroundO6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated.MethodsThe associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case-control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown.ResultsWe found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39-0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40-0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27-0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35-0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21-0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population.ConclusionsThe study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.
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