2. Academic Validation
  3. Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination

Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination

  • Cell Mol Life Sci. 2024 Aug 19;81(1):355. doi: 10.1007/s00018-024-05392-z.
Huidi Yu 1,  Yuling Sun 1,  Jingting Zhang 1,  Wenhui Zhang 1,  Wei Liu 1,  Penggang Liu 1,  Kaituo Liu 2,  Jing Sun 1,  Hailiang Liang 3,  Pinghu Zhang 4,  Xiaoquan Wang 5,  Xiufan Liu 5,  Xiulong Xu 6 7 8
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
  • 2 Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou, 225009, Jiangsu Province, China.
  • 3 Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
  • 4 College of Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
  • 5 Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
  • 6 College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn.
  • 7 Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn.
  • 8 Jiangsu Coinnovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn.
PMID: 39158695 DOI: 10.1007/s00018-024-05392-z
Abstract

Caspase-8, an aspartate-specific cysteine Protease that primarily functions as an initiator Caspase to induce Apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with Caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether Caspase-8 enhances or suppresses Antiviral responses against influenza A virus (IAV) Infection remains to be determined. Here, we report that Caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, Caspase-8 deficiency and two Caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate Antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-β, MX1, and ISG15 gene expression; and decreased IFN-β production but increased virus replication. Mechanistically, Caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a Deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate Antiviral immunity. Neither Caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or Antiviral innate immunity. Our study provides evidence that Caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

Keywords

CYLD; Caspase-8; Influenza A virus; Innate immunity; RIPK1.

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