Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity - PubMed (original) (raw)

. 2021 Oct 21;81(20):4147-4164.e7.

doi: 10.1016/j.molcel.2021.07.040. Epub 2021 Aug 27.

Zhengyang Yu 2, Dan Zhang 3, Shasha Chen 4, Hongxin Guan 5, Ruyuan Zhou 6, Qirou Wu 2, Qian Zhang 6, Shengduo Liu 3, Mukesh Kumar Venkat Ramani 7, Bing Yang 2, Xiao-Qun Ba 8, Jing Zhang 8, Jun Huang 2, Xueli Bai 9, Jun Qin 10, Xin-Hua Feng 11, Songying Ouyang 5, Yan Jessie Zhang 7, Tingbo Liang 12, Pinglong Xu 13

Affiliations

• PMID: 34453890
• DOI: 10.1016/j.molcel.2021.07.040

Free article

Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity

Fansen Meng et al. Mol Cell. 2021.

Free article

Abstract

Missense mutations of the tumor suppressor Neurofibromin 2 (NF2/Merlin/schwannomin) result in sporadic to frequent occurrences of tumorigenesis in multiple organs. However, the underlying pathogenicity of NF2-related tumorigenesis remains mostly unknown. Here we found that NF2 facilitated innate immunity by regulating YAP/TAZ-mediated TBK1 inhibition. Unexpectedly, patient-derived individual mutations in the FERM domain of NF2 (NF2m) converted NF2 into a potent suppressor of cGAS-STING signaling. Mechanistically, NF2m gained extreme associations with IRF3 and TBK1 and, upon innate nucleic acid sensing, was directly induced by the activated IRF3 to form cellular condensates, which contained the PP2A complex, to eliminate TBK1 activation. Accordingly, NF2m robustly suppressed STING-initiated antitumor immunity in cancer cell-autonomous and -nonautonomous murine models, and NF2m-IRF3 condensates were evident in human vestibular schwannomas. Our study reports phase separation-mediated quiescence of cGAS-STING signaling by a mutant tumor suppressor and reveals gain-of-function pathogenesis for NF2-related tumors by regulating antitumor immunity.

Keywords: Hippo-YAP; IRF3; NF2; TBK1; antitumor immunity; cGAS-STING; innate immunity; liquid-liquid phase separation; schwannomas; tumor suppressor.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

• Interferon induction held captive in tumor cells.
  Bridgeman A, Rehwinkel J. Bridgeman A, et al. Mol Cell. 2021 Oct 21;81(20):4109-4110. doi: 10.1016/j.molcel.2021.10.004. Mol Cell. 2021. PMID: 34686311

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