Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response

• DOI: 10.7554/elife.14087
• Publication Date: 2016-04-11T13:13:27Z
• Authors: Zhou Yu; Taoyong Chen; Xuelian Li; Mingjin Yang; Songqing Tang; Xuhui Zhu; Yan Gu; Xiaoping Su; Meng Xia; Weihua Li; Xuemin Zhang; Qingqing Wang; Xuetao Cao; Jianli Wang
• Keywords: QH301-705.5; SCF complex; Science; Immunology; Herpesvirus 1, Human; MAP Kinase Kinase Kinase 5; Cell Line; antiviral response; Mice; 03 medical and health sciences; Animals; Humans; Biology (General); innate immunity; S-Phase Kinase-Associated Proteins; 0303 health sciences; F-Box Proteins; Macrophages; Q; R; JNK Mitogen-Activated Protein Kinases; Herpes Simplex; Cullin Proteins; Immunity, Innate; 3. Good health; Mice, Inbred C57BL; ASK1; Disease Models, Animal; HEK293 Cells; Gene Expression Regulation; Host-Pathogen Interactions; Interferon Type I; Medicine; Fbxo21; polyubiquitination; Signal Transduction

Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1–Cul1–F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.