2. Academic Validation
  3. Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies

Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies

  • Cell Death Dis. 2022 Aug 24;13(8):731. doi: 10.1038/s41419-022-05156-2.
Di Wu 1,  Zhaowei Wang 2,  Jing Zhang 3 4,  Adam G Robinson 3,  Bao Lyu 1 5,  Ziyu Chen 1,  Chong Wang 1,  Bin Wei 1 5,  Xiaojun Xia 6,  Qing Zhang 3 4 7,  Xi Zhou 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 2 State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
  • 4 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
  • 7 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 8 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China. zhouxi@wh.iov.cn.
  • 9 University of Chinese Academy of Sciences, Beijing, 100049, China. zhouxi@wh.iov.cn.
PMID: 36002459 DOI: 10.1038/s41419-022-05156-2
Abstract

Host organisms use different innate immune mechanisms to defend against pathogenic infections, while tight control of innate immunity is essential for proper immune induction and balance. Here, we reported that apoptotic induction or Caspase-3 overexpression caused dramatic reduction of differently triggered cytokine signalings in human cells, murine primary cells and mouse model, while the loss of Caspase-3 or inhibiting Apoptosis markedly enhances these immune signalings. Furthermore, Caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity. And the caspase-3-resistant p65/RelA, RelB, or c-Rel mutant mostly restored the caspase-3-induced suppression of cytokine production. Interestingly, we further uncovered that apoptotic induction also dramatically inhibited Toll immune signaling in Drosophila, and the Drosophila effector caspases, drICE and DCP-1, also mediated the degradation of DIF, the NF-κB of Toll signaling. Together, our findings demonstrate apoptotic effector caspases, including mammalian Caspase-3 and fly drICE/DCP-1, can function as repressors of NF-κB-mediated innate immune signalings.

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