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

Yu, Huidi; Sun, Yuling; Zhang, Jingting; Zhang, Wenhui; Liu, Wei; Liu, Penggang; Liu, Kaituo; Sun, Jing; Liang, Hailiang; Zhang, Pinghu; Wang, Xiaoquan; Liu, Xiufan; Xu, Xiulong

Yu, Huidi; Sun, Yuling; Zhang, Jingting; Zhang, Wenhui; Liu, Wei; Liu, Penggang; Liu, Kaituo; Sun, Jing; Liang, Hailiang; Zhang, Pinghu; Wang, Xiaoquan; Liu, Xiufan; Xu, Xiulong.

Afiliación

Yu H; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Sun Y; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Zhang J; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Zhang W; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Liu W; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Liu P; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Liu K; Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou, 225009, Jiangsu Province, China.
Sun J; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Liang H; Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Zhang P; College of Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
Wang X; Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
Liu X; Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
Xu X; College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn.

Cell Mol Life Sci ; 81(1): 355, 2024 Aug 19.

Article en En | MEDLINE | ID: mdl-39158695

ABSTRACT

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-ß, MX1, and ISG15 gene expression; and decreased IFN-ß 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.

Asunto(s)

Caspasa 8; Proteína 58 DEAD Box; Enzima Desubiquitinante CYLD; Inmunidad Innata; Virus de la Influenza A; Gripe Humana; Quinasas Quinasa Quinasa PAM; Ubiquitinación; Humanos; Enzima Desubiquitinante CYLD/metabolismo; Enzima Desubiquitinante CYLD/genética; Caspasa 8/metabolismo; Caspasa 8/genética; Quinasas Quinasa Quinasa PAM/metabolismo; Quinasas Quinasa Quinasa PAM/genética; Quinasas Quinasa Quinasa PAM/inmunología; Virus de la Influenza A/inmunología; Proteína 58 DEAD Box/metabolismo; Proteína 58 DEAD Box/genética; Proteína 58 DEAD Box/inmunología; Gripe Humana/inmunología; Gripe Humana/virología; Células A549; Animales; Transducción de Señal/inmunología; Receptores Inmunológicos

Palabras clave

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

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Virus de la Influenza A / Quinasas Quinasa Quinasa PAM / Gripe Humana / Caspasa 8 / Ubiquitinación / Proteína 58 DEAD Box / Enzima Desubiquitinante CYLD / Inmunidad Innata Límite: Animals / Humans Idioma: En Revista: Cell Mol Life Sci Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza

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