The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling

  • Cell Host Microbe. 2014 Oct 8;16(4):450-61. doi: 10.1016/j.chom.2014.09.006.
Qian Zhou  1 ,  Heng Lin  1 ,  Suyun Wang  2 ,  Shuai Wang  1 ,  Yong Ran  2 ,  Ying Liu  1 ,  Wen Ye  1 ,  Xiaozhe Xiong  1 ,  Bo Zhong  1 ,  Hong-Bing Shu  3 ,  Yan-Yi Wang  4
Affiliations
  • 1. Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 2. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
  • 3. Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China. Electronic address: [email protected].
PMID: 25299331 DOI: 10.1016/j.chom.2014.09.006
Abstract

Viral DNA sensing within the cytosol of infected cells activates type I interferon (IFN) expression. MITA/STING plays an essential role in this pathway by acting as both a sensor for the second messenger cGAMP and as an adaptor for downstream signaling components. In an expression screen for proteins that can activate the IFNB1 promoter, we identified the ER-associated protein ZDHHC1 as a positive regulator of virus-triggered, MITA/STING-dependent immune signaling. Zdhhc1(-/-) cells failed to effectively produce IFNs and Other cytokines in response to Infection with DNA but not RNA viruses. Zdhhc1(-/-) mice infected with the neurotropic DNA virus HSV-1 exhibited lower cytokine levels and higher virus titers in the brain, resulting in higher lethality. ZDHHC1 constitutively associated with MITA/STING and mediates dimerization/aggregation of MITA/STING and recruitment of the downstream signaling components TBK1 and IRF3. These findings support a role for ZDHHC1 in mediating MITA/STING-dependent innate immune response against DNA viruses.