Interferon-stimulated gene products as regulators of central carbon metabolism.

Kourosh H Ebrahimi,Javier Gilbert‐Jaramillo,William S James,James S.O Mccullagh

doi:10.1111/febs.15625

Kourosh H Ebrahimi, Javier Gilbert‐Jaramillo + Show 2 more

Open Access

https://doi.org/10.1111/febs.15625

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Journal: FEBS Journal	Publication Date: Dec 1, 2020
Citations: 9	License type: CC BY 4.0

Affiliation: University of Oxford

Abstract

In response to viral infections, the innate immune system rapidly activates expression of several interferon-stimulated genes (ISGs), whose protein and metabolic products are believed to directly interfere with the viral life cycle. Here, we argue that biochemical reactions performed by two specific protein products of ISGs modulate central carbon metabolism to support a broad-spectrum antiviral response. We demonstrate that the metabolites generated by metalloenzymes nitric oxide synthase and the radical S-adenosylmethionine (SAM) enzyme RSAD2 inhibit the activity of the housekeeping and glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). We discuss that this inhibition is likely to stimulate a range of metabolic and signalling processes to support a broad-spectrum immune response. Based on these analyses, we propose that inhibiting GAPDH in individuals with deteriorated cellular innate immune response like elderly might help in treating viral diseases such as COVID-19.

Highlights

Central carbon metabolism converts sugars into a range of metabolic precursors that are used to generate biomass and energy required for the cellular function [1] (Fig. 1A)
We suggest that the metabolites generated by some interferon-stimulated gene (ISG) proteins contribute to the remodelling of the central carbon metabolism in support of a broad-spectrum antiviral immune response
We show how the early metabolites generated by the biochemical reactions of two ISG metalloenzymes, namely nitric oxide synthase (NOS) and the radical-SAM enzyme RSAD2, inhibit the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and how this inhibition is likely to support a broad-spectrum antiviral immune response

Summary

Introduction

Central carbon metabolism converts sugars into a range of metabolic precursors that are used to generate biomass and energy required for the cellular function [1] (Fig. 1A). When an infectious agent enters the factory, it will highjack the main process and use the products for its reproduction Under this circumstance, the first response of the control room would be to use some of the available products in a second reaction (analogous to the function of ISGs) to directly. We suggest that the metabolites generated by some ISG proteins contribute to the remodelling of the central carbon metabolism in support of a broad-spectrum antiviral immune response. We show how the early metabolites generated by the biochemical reactions of two ISG metalloenzymes, namely nitric oxide synthase (NOS) and the radical-SAM enzyme RSAD2, inhibit the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and how this inhibition is likely to support a broad-spectrum antiviral immune response

Mechanisms adopted by cells to inhibit GAPDH

Inhibition of GAPDH and a broadspectrum antiviral response