LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

Xiu-Ying Gong; Qi-Min Zhang; Xiang Zhao; Yi-Lin Li; Zi-Ling Qu; Zhi Li; Cheng Dan; Jian-Fang Gui; Yi-Bing Zhang

doi:10.1016/j.isci.2022.104821

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

iScience. 2022 Jul 30;25(8):104821. doi: 10.1016/j.isci.2022.104821. eCollection 2022 Aug 19.

Authors

Xiu-Ying Gong^{1

2}, Qi-Min Zhang^{1

2}, Xiang Zhao^{1

2}, Yi-Lin Li^{1

2}, Zi-Ling Qu^{1

2}, Zhi Li¹, Cheng Dan^{1

2}, Jian-Fang Gui^{1

2

3}, Yi-Bing Zhang^{1

2

3}

Affiliations

¹ State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
² University of Chinese Academy of Sciences, Beijing 10049, China.
³ The Innovation Academy of Seed Design, Chinese Academy of Sciences, Wuhan 430072, China.

Abstract

In mammals, LGP2 is the enigmatic RLR family member, being initially believed as an inhibitor of RLR-triggered IFN response but subsequently as an activator of MDA5 signaling and an inhibitor of RIG-I signaling. The contradiction happens to fish LGP2. Here, we generate a lgp2 loss-of-function (lgp2 ^lof/lof ) zebrafish mutant, which is highly susceptible to SVCV infection, displaying an initially decreased activation of IFN response and a following increased one. Mechanistically, zebrafish LGP2 functions as the essential activator of IFN response dependent on MDA5 at the early stage of viral infection but as a negative regulator by impairing mRNA levels of tbk1 and ikki at the late stage of viral infection. The function switch of LGP2 is related to cellular IFN production during viral infection. Our data demonstrate that zebrafish LGP2 is a key homeostatic regulator of IFN response and thus essential for zebrafish survival against SVCV infection.

Keywords: Biochemistry; Immunology; Virology.