ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy

Abstract

Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.

Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake

“…Our results also substantiate a general role for the core ATG machinery and for autophagosome formation in facilitating glucose metabolism, rather than a specialized function mediated by individual autophagy regulators. Recently, the autophagy regulator ULK1/2 was reported to directly control the activities of several glycolytic enzymes independently of the core autophagic machinery during amino acid starvation (Li et al, 2016). However, these studies were predominantly conducted using saline-induced amino acid starvation, which causes a severe reduction in glycolytic activity; in this context, ULK loss-of-function led to a further drop in glycolysis.…”

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

“…Conversely, upon starvation, mTORC1 activity is reduced, alleviating the repression of ULK1/2. Active ULK1/2 is then able to phosphorylate key glycolytic enzymes and initiate autophagy in a bid to sustain glycolysis, maintaining cellular energy and redox homeostasis (Li et al, 2016) …”

Canonical and noncanonical functions of ULK/Atg1

“…First, ULK1/2 phosphorylates key glycolytic enzymes (i.e., hexokinase, phosphofructokinase 1, and enolase 1) and a gluconeogenic enzyme (i.e., fructose-1,6-bisphosphatase) to secure carbon flux into the pentose phosphate pathway and maintain cellular energy [76••]. Silencing other key autophagy genes (e.g., Atg5 , Atg7 , and Beclin-1 ) does not recapitulate the effect of ULK1/2 deficiency on glucose consumption under the same conditions [76••], dissociating this function from its role in autophagy.…”

“…Silencing other key autophagy genes (e.g., Atg5 , Atg7 , and Beclin-1 ) does not recapitulate the effect of ULK1/2 deficiency on glucose consumption under the same conditions [76••], dissociating this function from its role in autophagy. ULK1 and ULK2 have both been implicated in fatty acid metabolism in adipocytes [77].…”