Grass Carp (Ctenopharyngodon idella) KAT8 Inhibits IFN 1 Response Through Acetylating IRF3/IRF7.

Meifeng Li,Dongming Li,Xiaowen Xu,Chengyu Hu,Zhichao Sun,Zeyin Jiang,Tingting Yu,Huiling Mao,Jihuan Hu

doi:10.3389/fimmu.2021.808159

Abstract

Post-translational modifications (PTMs), such as phosphorylation and ubiquitination, etc., have been reported to modulate the activities of IRF3 and IRF7. In this study, we found an acetyltransferase KAT8 in grass carp (CiKAT8, MW286472) that acetylated IRF3/IRF7 and then resulted in inhibition of IFN 1 response. CiKAT8 expression was up-regulated in the cells under poly I:C, B-DNA or Z-DNA stimulation as well as GCRV(strain 873) or SVCV infection. The acetyltransferase domain (MYST domain) of KAT8 promoted the acetylation of IRF3 and IRF7 through the direct interaction with them. So, the domain is essential for KAT8 function. Expectedly, KAT8 without MYST domain (KAT8-△264-487) was granularly aggregated in the nucleus and failed to down-regulate IFN 1 expression. Subcellular localization analysis showed that KAT8 protein was evenly distributed in the nucleus. In addition, we found that KAT8 inhibited the recruitment of IRF3 and IRF7 to ISRE response element. Taken together, our findings revealed that grass carp KAT8 blocked the activities of IRF3 and IRF7 by acetylating them, resulting in a low affinity interaction of ISRE response element with IRF3 and IRF7, and then inhibiting nucleic acids-induced innate immune response.

Highlights

Innate immunity is the early line of defense against microbial infection in cell
The post-translational modifications (PTMs) of innate immune signaling molecules affect their activities in signal transduction, which are critical in regulating the expression of type I interferon [3,4,5]
We found grass carp KAT8 interacted with IRF3 and IRF7 and acetylated them, resulting in a weak interaction between IRF3/IRF7 and interferon-sensitive response element (ISRE) within target gene, suppressing IFN 1 expression

Summary

Introduction

Innate immunity is the early line of defense against microbial infection in cell. It recognizes and eliminates pathogenic molecules through its pattern recognition receptors [1, 2]. Several negative regulators are required in innate immune response. The post-translational modifications (PTMs) of innate immune signaling molecules affect their activities in signal transduction, which are critical in regulating the expression of type I interferon [3,4,5]. RNF5 negatively regulates the antiviral response by mediating the ubiquitination and degradation of MITA [13]. RIG-I and MDA5 are SUMOylated by tripartite motif-containing protein 38 (TRIM38) in uninfected or early infected cells to ensure their optimal activation [17]

Methods

Results

Conclusion