Work

Golgi-localised Guanylate-binding protein 5 enhances glycolysis in macrophages

Year: 2026

Type: preprint

Abstract: ABSTRACT Guanylate-binding proteins (GBPs) are part of a family of large interferon gamma (IFNψ)-inducible GTPases, with ascribed roles in infection control and induction of programmed cell death. While pathogen-specific functions of GBPs have been studied in detail, their broader regulation of frontline immune defences remain unexplored. Here, we analysed the global contribution of human GBP1-5 to cellular metabolism in IFNψ-stimulated macrophages. We found a robust role of GBP2 and GBP5 in macrophage glycolysis. Only GBP5, and not GBP2 deficiency impaired surface expression and cytokine production of classically IFNψ/LPS-activated macrophages. The GTPase activity of GBP5 was required for the regulation of glycolysis and cytokine production. We found that GBP5 deficiency impaired cellular glucose uptake and lactate production specifically. Isotopic tracing with [U- 13 C 6 ]-Glucose confirmed a decrease in several glycolytic intermediates, including glucose 6-phosphate, pyruvate, and lactate, but stable levels of traced tricarboxylic acid cycle (TCA) intermediates. Elevated ribose-5-phosphate and glycerol levels suggest an altered cytosolic redox balance and enhanced breakdown of fatty acids. GBP5 localised predominantly to the cis-Golgi and in the absence of GBP5 we observed increased Golgi fragmentation, however the total Golgi size remained unchanged. Our results underscore the fundamental role of GBP5 in glycolytic fluxes and Golgi integrity in IFNψ-stimulated macrophages, highlighting its significance in immune function in general and immunometabolism specifically.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.02.17.706357