TY - JOUR
T1 - Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation
AU - Wang, Meiyue
AU - Flaswinkel, Heinrich
AU - Joshi, Abhinav
AU - Napoli, Matteo
AU - Masgrau-Alsina, Sergi
AU - Kamper, Julia M.
AU - Henne, Antonia
AU - Heinz, Alexander
AU - Berouti, Marleen
AU - Schmacke, Niklas A.
AU - Hiller, Karsten
AU - Kremmer, Elisabeth
AU - Wefers, Benedikt
AU - Wurst, Wolfgang
AU - Sperandio, Markus
AU - Ruland, Jürgen
AU - Fröhlich, Thomas
AU - Hornung, Veit
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.
AB - Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.
UR - http://www.scopus.com/inward/record.url?scp=85200293660&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-50104-7
DO - 10.1038/s41467-024-50104-7
M3 - Article
C2 - 39085210
AN - SCOPUS:85200293660
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6438
ER -