SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure

Abstract

Alcohol abuse, reported by 1/8th critically ill patients, is an independent risk factor for death in sepsis. Sepsis kills over 270,000 patients/year in the US. We reported that the ethanol-exposure suppresses innate-immune response, pathogen clearance, and decreases survival in sepsis-mice via sirtuin 2 (SIRT2). SIRT2 is an NAD+-dependent histone-deacetylase with anti-inflammatory properties. We hypothesized that in ethanol-exposed macrophages, SIRT2 suppresses phagocytosis and pathogen clearance by regulating glycolysis. Immune cells use glycolysis to fuel increased metabolic and energy demand of phagocytosis. Using ethanol-exposed mouse bone marrow- and human blood monocyte-derived macrophages, we found that SIRT2 mutes glycolysis via deacetylating key glycolysis regulating enzyme phosphofructokinase-platelet isoform (PFKP), at mouse lysine 394 (mK394, human: hK395). Acetylation of PFKP at mK394 (hK395) is crucial for PFKP function as a glycolysis regulating enzyme. The PFKP also facilitates phosphorylation and activation of autophagy related protein 4B (Atg4B). Atg4B activates microtubule associated protein 1 light chain-3B (LC3). LC3 is a driver of a subset of phagocytosis, the LC3-associated phagocytosis (LAP), which is crucial for segregation and enhanced clearance of pathogens, in sepsis. We found that in ethanol-exposed cells, the SIRT2-PFKP interaction leads to decreased Atg4B-phosphorylation, decreased LC3 activation, repressed phagocytosis and LAP. Genetic deficiency or pharmacological inhibition of SIRT2 reverse PFKP-deacetylation, suppressed LC3-activation and phagocytosis including LAP, in ethanol-exposed macrophages to improve bacterial clearance and survival in ethanol with sepsis mice.

The SIRT2-AMPK axis regulates autophagy induced by acute liver failure

“…Previous studies have shown that deletion of SIRT2 reduces the AMPK response to metformin in mice treated with Ang II in the mice model of pathological cardiac hypertrophy 18 . In acute ethanol-exposed macrophages, knockdown of SIRT2 led to increasing LC3 activation 38 . SIRT2 inhibitor NCO-90/14 increases autophagosome accumulation and LC3-II levels in cell lines 39 .…”

Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma

“…PFKP influenced stimulation of monocytes with oxidized low-density lipoprotein ( 73 ) and the expression level was correlated with interferon-gamma (IFN-γ) expression level ( 74 ). Sirtuin 2-PFKP interaction led to decreased light chain-3B activation and repressed phagocytosis ( 75 ). PFKP induced PD-L1 expression through EGFR activation and promoted immune evasion in human glioblastoma cells ( 76 ).…”

Identification of qualitative characteristics of immunosuppression in sepsis based on immune-related genes and immune infiltration features

“…Several studies have proposed that various risk factors, such as thrombocytopenia [ 7 , 8 ] and alcohol abuse [ 9 ], contribute to the mortality of sepsis patients. Immunosuppression, particularly post-clinical 'recovery,' has been identified as a crucial factor [ [10] , [11] , [12] , [13] ].…”