The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response

Sci Signal. 2015 Aug 4;8(388):ra78. doi: 10.1126/scisignal.aab1883.

Abstract

Viral infection activates host defense mechanisms, including the production of type I interferon (IFN) and the apoptosis of infected cells. We investigated whether these two antiviral responses were differentially regulated in infected cells. We showed that the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) apoptosis signal-regulating kinase 1 (ASK1) was activated in cells by the synthetic double-stranded RNA analog polyinosinic:polycytidylic acid [poly(I:C)] and by RNA viruses, and that ASK1 played an essential role in both the induction of the gene encoding IFN-β (IFNB) and apoptotic cell death. In contrast, we found that the MAPKKK ASK2, a modulator of ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing IFNB expression. Furthermore, genetic deletion of either ASK1 or ASK2 in mice promoted the replication of influenza A virus in the lung. These results indicated that ASK1 and ASK2 are components of the antiviral defense mechanism and suggested that ASK2 acts as a key modulator that promotes apoptosis rather than the type I IFN response. Because ASK2 is selectively present in epithelium-rich tissues, such as the lung, ASK2-dependent apoptosis may contribute to an antiviral defense in tissues with a rapid repair rate in which cells could be readily replaced.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Blotting, Western
  • Cells, Cultured
  • Dogs
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Interferon-beta / genetics*
  • Interferon-beta / metabolism
  • Lung / metabolism
  • Lung / virology
  • MAP Kinase Kinase Kinase 5 / genetics*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Kinase Kinases / genetics*
  • MAP Kinase Kinase Kinases / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice, Knockout
  • Microscopy, Confocal
  • Models, Genetic
  • Poly I-C / genetics
  • RNA Interference
  • RNA Virus Infections / genetics
  • RNA Virus Infections / metabolism
  • RNA Virus Infections / virology
  • RNA Viruses / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Survival Analysis

Substances

  • Interferon-beta
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 6
  • Poly I-C