G-CSF reshapes the cytosolic PCNA scaffold and modulates glycolysis in neutrophils

Aymonnier, K; Bosetta, E; Leborgne, NGF; Ullmer, A; Le Gall, M; De Chiara, A; Salnot, V; Mani, S; Scapini, P; Wicks, I; Chatfield, S; Martin, KR; Witko-Sarsat, V

Author(s): Aymonnier, K; Bosetta, E; Leborgne, NGF; Ullmer, A; Le Gall, M; De Chiara, A; Salnot, V; Mani, S; Scapini, P; Wicks, I; Chatfield, S; Martin, KR; Witko-Sarsat, V;
Details: Publication Year 2024-10-12,Volume 115,Issue #2,Page 205-221
Journal Title: Journal of Leukocyte Biology
Abstract: Cytosolic proliferating cell nuclear antigen (PCNA) is involved in neutrophil survival and function, where it acts as a scaffold and associates with proteins involved in apoptosis, NADPH oxidase activation, cytoskeletal dynamics and metabolism. While the PCNA interactome has been characterized in neutrophils under homeostatic conditions, less is known about neutrophil PCNA in pathophysiological contexts. G-CSF is a cytokine produced in response to inflammatory stimuli, that regulates many aspects of neutrophil biology. Here we used isolated normal density neutrophils from G-CSF-treated haemopoietic stem cell donors (GD) as a model to understand the role of PCNA during inflammation. Proteomic analysis of the neutrophil cytosol revealed significant differences between GD and healthy donors (HD). PCNA was one of the most upregulated proteins in GD and the PCNA interactome was significantly different in GD compared to HD. Importantly, while PCNA associated with almost all enzymes involved in glycolysis in HD, these associations were decreased in GD. Functionally, neutrophils from GD had a significant increase in glycolysis compared to HD. Using p21 competitor peptides, we showed that PCNA negatively regulates neutrophil glycolysis in HD, but had no effect on GD neutrophils. These data demonstrate that G-CSF alters the PCNA scaffold, affecting interactions with key glycolytic enzymes and thus regulates glycolysis, the main energy pathway utilized by neutrophils. By this selective control of glycolysis, PCNA can organize neutrophils functionality in parallel with other PCNA mechanisms of prolonged survival. PCNA may therefore be instrumental in the reprogramming that neutrophils undergo in inflammatory or tumoral settings.
Publisher: Oxford Academic
Keywords: G-csf; Pcna; glycolysis; neutrophil; survival
Research Division(s): Inflammation
PubMed ID: 37824822
Publisher's Version: https://doi.org/10.1093/jleuko/qiad122
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-15 05:00:02

Last Modified: 2024-01-25 09:15:54