2. Academic Validation
  3. The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response

The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response

  • Cell Discov. 2021 Jun 22;7(1):46. doi: 10.1038/s41421-021-00277-y.
Chen Li 1,  Lu Feng 1,  Wei-Wei Luo 2,  Cao-Qi Lei 1,  Mi Li 1,  Hong-Bing Shu 3
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Research Unit of Innate Immune and Inflammatory Diseases of Chinese Academy of Medical Sciences, Wuhan University, Wuhan, Hubei, China.
  • 2 Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei, Wuhan, China.
  • 3 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Research Unit of Innate Immune and Inflammatory Diseases of Chinese Academy of Medical Sciences, Wuhan University, Wuhan, Hubei, China. shuh@whu.edu.cn.
PMID: 34155193 DOI: 10.1038/s41421-021-00277-y
Abstract

MITA (also known as STING) is an ER-located adaptor protein, which mediates DNA-triggered innate immune response and is critically involved in autoimmune diseases and tumorigenesis. MITA is regulated by post-translational modifications, but how post-transcriptional mechanisms are involved in the regulation of MITA is still largely unknown. Here, we identified the RNA-binding protein LUC7L2 as a negative regulator of DNA virus-triggered innate immune response. LUC7L2-deficient mice exhibited resistance to lethal herpes simplex virus 1 (HSV-1) Infection and reduced HSV-1 loads in the brain. Mechanistically, LUC7L2 directly bound to intron 3 of MITA precursor messenger RNA, inhibited its splicing and promoted its nonsense-mediated decay, leading to its downregulation at protein level. LUC7L2-deficient cells had markedly increased MITA level, leading to heightened innate Antiviral response. Finally, LUC7L2 was induced following HSV-1 Infection. Our findings reveal a feedback negative post-transcriptional regulatory mechanism for regulation of MITA-mediated innate immune response to viral and aberrant cellular DNA.

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