ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation

Abstract

Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these processes is poorly understood. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is activated upon UNC-51–like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients are scarce and promotes lactate production. Lactate connects autophagy and glycolysis through Vps34 lactylation (at lysine-356 and lysine-781), which is mediated by the acyltransferase KAT5/TIP60. Vps34 lactylation enhances the association of Vps34 with Beclin1, Atg14L, and UVRAG, and then increases Vps34 lipid kinase activity. Vps34 lactylation promotes autophagic flux and endolysosomal trafficking. Vps34 lactylation in skeletal muscle during intense exercise maintains muscle cell homeostasis and correlates with cancer progress by inducing cell autophagy. Together, our findings describe autophagy regulation mechanism and then integrate cell autophagy and glycolysis.

Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation

“…Indeed, HEK293T cells treated with various concentrations of lactate showed a dose-dependent induction of α-tubulin lactylation (Extended Data Fig. 3a, b), consistent with previous reports indicating that lactate enhances protein lactylation 27,32,35,44 . Similarly, GSKA, an inhibitor of lactate dehydrogenase (LDH) designed to prevent lactate production, reduced α-tubulin lactylation (Extended Data Fig.…”

“…HDAC6 functions as a primary "writer" for α-tubulin lactylation Previous studies have indicated that acetyltransferases may also catalyze protein lactylation 27,29,32 . To identify the protein responsible for α-tubulin lactylation, we transfected various acetyltransferases into HEK293T cells and assessed α-tubulin lactylation levels.…”

“…Recent studies have discovered a new post-translational modi cation named protein lactylation, targeting lysine residues in both histones and non-histone proteins [27][28][29][30] . Acetyltransferases such as p300 or TIP60 have been shown to lactylate proteins by using lactyl-coenzyme A (Lac-CoA) as donor 27,31,32 .…”

Hypoxia‐sensing VGLL4 promotes LDHA‐driven lactate production to ameliorate neuronal dysfunction in a cellular model relevant to Alzheimer's disease

“…More recently, it has been reported that the timed degradation of lactate‐kinetic cell cycle proteins directly regulates protein function, thereby controlling the biochemical mechanisms of cell cycle and proliferation 57 . Furthermore, lactate mediates lactylation modification of type III phosphatidylinositol kinase (Vps34) lysine catalyzed by acyltransferases, thereby increasing its kinase activity, which in turn promotes the occurrence of autophagy and the endosomal‐lysosomal degradation pathway 58 . Notably, as a metabolite and regulator of the central nervous system, lactate has a wide range of effects on neurodegenerative diseases 59 .…”

“…57 Furthermore, lactate mediates lactylation modification of type III phosphatidylinositol kinase (Vps34) lysine catalyzed by acyltransferases, thereby increasing its kinase activity, which in turn promotes the occurrence of autophagy and the endosomal-lysosomal degradation pathway. 58 Notably, as a metabolite and regulator of the central nervous system, lactate has a wide range of effects on neurodegenerative diseases. 59 In this study, we observed that VGLL4 promoted lactate production while concurrently reduced APP amyloidogenic processing and ameliorated neuronal synaptic damage (Figures 3 and 5).…”