Abstract
cGAS/DncV-like nucleotidyltransferase (CD-NTase) family members are immune sensors that synthesize diverse nucleotide signals to initiate antiviral response in bacteria and animals. As a founding member of CD-NTase enzyme, cGAS has been identified as a key sensor for cytoplasmic DNA and type I interferons (IFNs) signaling in metazoan. However, the functions of other metazoan CD-NTases remain enigmatic. Here, we showed that Mab-21 domain-containing protein 2 (MB21D2), another member of the CD-NTase family, plays a positive role in modulating the cGAS-STING signaling in myeloid cells. Deficiency of MB21D2 in THP-1 cells or mice macrophages led to impaired production of type I interferon upon DNA stimulation. Consistently, Mb21d2−/− mice showed more susceptible to infection with DNA virus and faster growth of melanoma, compared to its counterparts. Mechanistically, MB21D2 specially bound with the N-terminal of cGAS, facilitated its liquid phase condensation and DNA-binding activity, leading to the enhanced production of cGAMP and subsequent IFN-β production. Thus, our findings unveiled that the CD-NTase family member MB21D2 contributes to host antiviral and antitumor responses by enhancing cGAS activation.
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Acknowledgements
This work was supported by grants from National key research and development program (2021YFC2300603) and the National Natural Science Foundation of China (32230033, 81930039, 31730026).
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CG conceived and supervised the study. HL, ZY and DZ performed the experiments. HX, FL, TC, H.Z, YZ, BL, LZ and WZ contributed to experimental design and discussion. HL, ZY and DZ analyzed the data. ZY, HL and CG wrote the manuscript.
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All animal studies were approved by the Scientific Investigation Board of School of Basic Medical Science, Shandong University (ECSBMSSDU2020-2-072).
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Liu, H., Yan, Z., Zhu, D. et al. CD-NTase family member MB21D2 promotes cGAS-mediated antiviral and antitumor immunity. Cell Death Differ 30, 992–1004 (2023). https://doi.org/10.1038/s41418-023-01116-1
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DOI: https://doi.org/10.1038/s41418-023-01116-1
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