How cells quickly activate innate immunity

02/07/2019

Upon infection cells manage to quickly switch from normal operation to immune reaction in a matter of minutes. This innate immunity requires a cellular signal cascade that activates antimicrobial or antiviral gene expression. Scientists led by Thomas Decker at the Max Perutz Labs have discovered that an alternative version of the activator of antimicrobial gene expression is constantly present on DNA. A molecular switch between the alternative and the regular version enables a quick onset of the immune response. The findings are published in the journal “Nature Communications”

Defense against pathogens is based on pre-existing and acquired mechanisms. Both innate and acquired immunity relies on signaling proteins called cytokines. A subgroup of these, called interferons dock on cell surface receptors to initiate a signaling process that causes the cell to activate genes responsible for immune defense against microbes. These signals stimulate activation of the protein complex ISGF3, responsible for initiating antimicrobial gene expression. The team of Thomas Decker now found out that two of the three proteins forming this complex are in fact constantly located at these genes, independently of the activating signals caused by interferons.

This ‘light’ version of ISGF3 maintains a low expression of antimicrobial genes, similar to an engine running in first gear. When activated by interferons, the complete version of ISGF3 complex assembles inside the nucleus, switching the gears and revving up the genetic machine of the innate immune system. The proximity of the proteins to the DNA and the rapid exchange of ‘light’ and complete versions explains how the innate immune system activates in such a quick manner, as Postdoctoral researcher and first author of the paper, Ekaterini Platanitis concludes: “When studying why antimicrobial gene expression is never completely switched off we were fascinated to find modular use of ISGF3 components as a way of switching between cellular alertness and immunological activation. This is a fascinating example of molecular economy. Cells maintain a low amount of innate immunity that does not interfere with their normal, healthy physiology. Upon infection the ISGF3 switch allows them to rapidly devote their entire genetic program to the combat against invading pathogens.”

Publication in Nature Communications: 

Ekaterini Platanitis, Duygu Demiroz, Anja Schneller, Katrin Fischer, Christophe Capelle, Markus Hartl, Thomas Gossenreiter, Mathias Müller, Maria Novatchkova & Thomas Decker 

A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription

doi.org/10.1038/s41467-019-10970-y