HDAC6-mediated PFKL deacetylation enhances aerobic glycolysis and promotes VSMC proliferation

TL;DR

This study shows that PFKL enzyme activity, regulated by HDAC6, promotes vascular smooth muscle cell growth and could be a target for treating vascular diseases.

Contribution

Identifies PFKL acetylation at K563 as a novel regulator of VSMC proliferation through HDAC6-mediated deacetylation.

Findings

PFKL acetylation is reduced in PDGF-BB-induced VSMCs.

HDAC6 deacetylates PFKL at K563, enhancing its activity and promoting VSMC proliferation.

PFKL K563R mutant increases VSMC proliferation, while K563Q mutant reduces it.

Abstract

Post-translational modifications (PTMs) of the glycolytic enzyme phosphofructokinase, liver type (PFKL) play a vital role in regulating its activity and function. Recently, we observed a reduction of PFKL acetylation in platelet-derived growth factor (PDGF)-BB-induced synthetic vascular smooth muscle cells (VSMCs). However, the function of acetylated PFKL has not been defined. This study aims to elucidate the effects and mechanisms of PFKL acetylation on the development and progression of vascular diseases. We found that the expression of PFKL is upregulated and its acetylation level is decreased in PDGF-BB-induced proliferative VSMCs. HDAC6, which acts as the deacetylase of PFKL, could interact with PFKL to enhance activity of PFKL by accelerating PFKL tetrameric formation and the aerobic glycolysis process, thereby promoting VSMC proliferation, which can be hindered through the application of HDAC inhibitor Trichostatin A (TSA) or siHDAC6. Site prediction and experimental validation revealed that K563 was the main PFKL acetylation site. The recombinant adenoviral vector carrying the PFKL K563R mutant aggravated, while the K563Q mutant attenuated PDGF-BB-induced VSMC proliferation and ligation-induced neointimal formation. Thus, PFKL may be a potential target for vascular reconstruction disease treatment.

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