• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • Glucose uptake a critical metabolic control point in


    Glucose uptake, a critical metabolic control point in glycolysis, is mediated by the GLUT (SLC2) family of integral membrane transporters (Mueckler and Thorens, 2013). GLUT1 (SLC2A1), one of the most well-studied members of the SLC2 family, exhibits a wide tissue distribution; cell surface expression of this transporter is increased during hypoxia and in diverse cancers exhibiting high levels of aerobic glycolysis (Warburg effect) (Carvalho et al., 2011). The kinetics of GLUT1 internalization, endosomal sorting, and recycling back to the plasma membrane play principal roles in maintaining glucose homeostasis in both normal and cancerous BRD-6125 (Eyster et al., 2009, Wieman et al., 2009, Wu et al., 2013). Importantly, the retromer complex, a protein assembly orchestrating the export of transmembrane proteins from early endosomes to the trans-Golgi network (TGN) or plasma membrane, is critical for GLUT1 recycling (Steinberg et al., 2013). In addition to promoting GLUT1 export to the cell surface, the retromer counteracts the trafficking and subsequent degradation of this nutrient transporter in the endolysosomal compartment. Here, we demonstrate that autophagy facilitates GLUT1 trafficking to the plasma membrane surface in a retromer-dependent manner and averts GLUT1 sorting into late endosomes and lysosomes. Finally, we uncover that autophagy is responsible for shuttling TBC1D5, a Rab GTPase-activating protein that interacts with both the retromer and LC3 (Popovic et al., 2012, Seaman et al., 2009), away from endosomal retromer complexes and toward LC3+ compartments. Relief of TBC1D5-mediated inhibition of the retromer at the early endosome via autophagosome induction promotes GLUT1 recycling and export to the cell surface. Therefore, BRD-6125 in response to diverse metabolic and oncogenic stresses, autophagy not only drives intracellular degradation to sustain core metabolic needs but also coordinates glucose uptake from the extracellular milieu by instructing the cell surface trafficking of a key nutrient transporter, GLUT1.
    Discussion Macroautophagy is traditionally viewed as a lysosomal degradation pathway in which autophagy-derived catabolic intermediates provide substrates for biosynthesis and energy production to promote cell survival. Here, we identify a role for autophagy in promoting glucose uptake from the extracellular environment via retromer-dependent cell surface trafficking of GLUT1. In contrast, autophagy does not impact downstream glycolytic events or the relative flux of carbon into the oxidative PPP, an early proximal side-branch of glycolytic metabolism. 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. In contrast, we now corroborate previous work demonstrating that in situations of high glycolytic demand, such as oncogenic Ras transformation and hypoxia, multiple ATGs are genetically required for increased glycolytic flux by promoting GLUT1 surface expression, thereby augmenting glucose uptake. Remarkably, autophagy status does not significantly impact glycolysis in non-transformed cells grown in nutrient-replete or normoxic conditions nor in response to rapamycin-mediated mTORC1 inhibition, thus illuminating a distinct requirement for autophagy in augmenting glycolytic phenotypes during specific metabolic and oncogenic contexts. GLUT1 internalization proceeds through both clathrin-dependent (CDE) and -independent (CIE) endocytosis pathways (Eyster et al., 2009, Wu et al., 2013). Thereafter, GLUT1-containing vesicles rapidly fuse with EEA1-positive vesicles, which are either delivered to the lysosome for degradation or recycled back to the membrane surface via tubular endosomes through the actions of multiple GTPases including Arf6 (Radhakrishna and Donaldson, 1997) and Rab22 (Weigert et al., 2004). We demonstrate here that genetic autophagy inhibition does not significantly impact GLUT1 internalization; instead, it distinctly compromises GLUT1 recycling back to the plasma membrane surface. Moreover, using live-cell imaging, we observe GLUT1 in tubulovesicular structures that traffic to the plasma membrane in autophagy-competent cells; in contrast, GLUT1 is trapped in the late endolysosomal compartment of autophagy-deficient cells. The early endocytic compartment, composed of thin tubular extensions and large vacuolar regions, serves as a major sorting hub for membrane proteins. However, transferrin receptor (TnFR) recycling via the early endocytic pathway is unaffected by genetic autophagy ablation, indicating that autophagy does not broadly impact early endosomal recycling pathways (Murrow et al., 2015).