Enzymatic independent role of sphingosine kinase 2 in regulating the expression of type I interferon during influenza A virus infection

PLoS Pathog. 2022 Sep 7;18(9):e1010794. doi: 10.1371/journal.ppat.1010794. eCollection 2022 Sep.

Abstract

Influenza virus has the ability to circumvent host innate immune system through regulating certain host factors for its effective propagation. However, the detailed mechanism is still not fully understood. Here, we report that a host sphingolipid metabolism-related factor, sphingosine kinase 2 (SPHK2), upregulated during influenza A virus (IAV) infection, promotes IAV infection in an enzymatic independent manner. The enhancement of the virus replication is not abolished in the catalytic-incompetent SPHK2 (G212E) overexpressing cells. Intriguingly, the sphingosine-1-phosphate (S1P) related factor HDAC1 also plays a crucial role in SPHK2-mediated IAV infection. We found that SPHK2 cannot facilitate IAV infection in HDAC1 deficient cells. More importantly, SPHK2 overexpression diminishes the IFN-β promoter activity upon IAV infection, resulting in the suppression of type I IFN signaling. Furthermore, ChIP-qPCR assay revealed that SPHK2 interacts with IFN-β promoter through the binding of demethylase TET3, but not with the other promoters regulated by TET3, such as TGF-β1 and IL6 promoters. The specific regulation of SPHK2 on IFN-β promoter through TET3 can in turn recruit HDAC1 to the IFN-β promoter, enhancing the deacetylation of IFN-β promoter, therefore leading to the inhibition of IFN-β transcription. These findings reveal an enzymatic independent mechanism on host SPHK2, which associates with TET3 and HDAC1 to negatively regulate type I IFN expression and thus facilitates IAV propagation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Influenza A virus
  • Influenza, Human* / enzymology
  • Interferon-beta* / genetics
  • Interferon-beta* / metabolism
  • Phosphotransferases (Alcohol Group Acceptor)* / metabolism
  • Virus Replication

Substances

  • Interferon-beta
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • sphingosine kinase 2, human

Grants and funding

This work was supported by the National Natural Science Foundation of China (81730061 to JW, 32070149 to HL), Guangdong Innovative and Entrepreneurial Research Team Program (2014ZT05S136 to HL), Project for Construction of Guangzhou Key Laboratory of Virology (201705030003 to JW), Youth Program of National Natural Science Foundation of China (31500137 to JC), and Guangdong Basic and Applied Basic Research Foundation (2019A1515011742 to CX). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.