2. Academic Validation
  3. TBK1-stabilized ZNF268a recruits SETD4 to methylate TBK1 for efficient interferon signaling

TBK1-stabilized ZNF268a recruits SETD4 to methylate TBK1 for efficient interferon signaling

  • J Biol Chem. 2023 Nov 3:105428. doi: 10.1016/j.jbc.2023.105428.
Yi Liu 1,  Wei Yin 1,  Xianhuang Zeng 2,  Jinhao Fan 3,  Chaozhi Liu 1,  Mingyu Gao 1,  Zan Huang 1,  Guihong Sun 4,  Mingxiong Guo 5
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, P.R. China.
  • 2 Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, Hubei, P.R. China.
  • 3 School of Ecology and Environment, Key Laboratory of Biodiversity and Environment on the Qinghai-Tibetan Plateau of Ministry of Education, Tibet University, Lhasa 850000, Tibet, P.R. China.
  • 4 Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, Hubei, P.R. China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, Hubei, P.R. China.
  • 5 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, P.R. China; School of Ecology and Environment, Key Laboratory of Biodiversity and Environment on the Qinghai-Tibetan Plateau of Ministry of Education, Tibet University, Lhasa 850000, Tibet, P.R. China. Electronic address: guomx@whu.edu.cn.
PMID: 37926288 DOI: 10.1016/j.jbc.2023.105428
Abstract

Sufficient activation of interferon signaling is critical for the host to fight against invading viruses, in which post-translational modifications have been demonstrated to play a pivotal role. Here, we demonstrate that human KRAB-zinc finger protein ZNF268a is essential for the virus-induced interferon signaling. We find that cytoplasmic ZNF268a is constantly degraded by lysosome thus remains low expressed in resting cell cytoplasm. Upon viral Infection, TBK1 interacts with cytosolic ZNF268a to catalyze the phosphorylation of Serine 178 of ZNF268a, which prevents the degradation of ZNF268a, resulting in the stabilization and accumulation of ZNF268a in the cytoplasm. Furthermore, we provide evidence that stabilized ZNF268a recruits the lysine methyltransferase SETD4 to TBK1 to induce the mono-methylation of TBK1 on lysine 607, which is critical for the assembly of the TBK1 signaling complex. Notably, ZNF268 S178 is conserved among higher primates but absent in rodents. Meanwhile, rodent TBK1 607th aa happens to be replaced by arginine, possibly indicating a species-specific role of ZNF268a in regulating TBK1 during evolution. These findings reveal novel functions of ZNF268a and SETD4 in regulating Antiviral interferon signaling.

Keywords

SETD4; TBK1 methylation; Virus-induced interferon signaling; ZNF268a.

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