Transient protein phosphorylation promotes disease tolerance to sepsis
Vivas, W.; Roth, J.; Willman, K.; Bouma, H. R.; Roestel, F.; Dlubatz, K.; Hirth, G.; Poempner, N.; Dau, T.; Cirri, E.; Zhang, S.; Peitzsch, M.; Chavakis, T.; Bauer, M.; Pannagiotou, G.; Moita, L.; Schaeuble, S.; Weis, S.
Show abstract
One of the enduring paradoxes of sepsis is that organs fail despite little evidence of irreversible tissue injury. Emerging evidence suggests that this state reflects a regulated metabolic shutdown within host tissues, yet whether such hypometabolism contributes to pathology or promotes survival remains unclear. This phenomenon resembles torpor, a physiological state of profound hypometabolism induced by environmental stress and mediated through reversible protein phosphorylation. Septic hypometabolism is identified here as a conserved tissue-specific metabolic adaptation which is characterized by transient activation of Glycogen Synthase Kinase (GSK)3{beta}. This activation reduced disease severity of bacterial sepsis without affecting the hosts pathogen burden, indicating that GSK3{beta} activity promotes disease tolerance to infection. Consistent with these findings, plasma signatures associated with GSK3{beta} inhibition correlated with worse clinical outcomes in patients with sepsis. Together, these results define septic hypometabolism as a torpor-like response and identify reversible phosphorylation as a key mechanism governing host adaptation to severe bacterial infection.
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