NF2 mutations are known to lead to tumorigenesis in numerous organs, which has generally been attributed to alterations in cell growth signaling pathways. Meng and colleagues suggested a novel role for NF2 in sensing cytoplasmic nucleic acids and mediating antiviral immune defenses. They showed that WT NF2 activated innate immunity via YAP/TAZ inhibition of the protein kinase TBK1, which normally phosphorylates and activates the pivotal interferon regulator IRF3. Clinical NF2 mutants lack this activity, instead exhibiting gain-of-function ability to suppress cGAS-STING signaling, further reducing antitumor immunity. Mechanistically, Meng and colleagues showed that NF2 mutants formed strong associations with IRF3 and TBK1, sequestering them from the cGAS-STING innate immunity machinery in liquid-liquid phase separated condensates. Stimulated by increased levels of cGAMP, activated IRF3 induced condensates via its increased affinity with the mutated FERM domain of the NF2 mutant. Importantly, these condensates could be visualized in patient-derived vestibular schwannomas.
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