The intricate relationship between metabolism and endocytic membrane traffic

Endocytic membrane traffic regulates the access of various proteins and other molecules to the extracellular milieu and, in doing so, impacts virtually every cellular process.1 Much has been revealed about the molecular and cellular mechanisms that operate within the endocytic system, spanning various routes of internalization from the cell surface2, 3 and sorting within a complex network of endosomes,4 resulting in the control of the trafficking of myriad receptors, channels and transporters, as well as fluid-phase uptake. Many seminal studies established the key contribution of endocytic membrane traffic to regulation of systemic and cell metabolism, such as the role of receptor-mediated endocytosis of low-density lipoproteins in systemic cholesterol homeostasis5-7 and the regulation of membrane traffic of glucose transporters impacting glucose homeostasis.8, 9 Many studies have since further revealed the intimate and intricate mutual regulation of cell and systemic metabolism and endocytic membrane traffic within various cells and tissues.10 In humans and other multicellular organisms, nutrient metabolism at the level of the organism is gated by a number of biological barriers, from intestinal epithelial cell layers tasked with nutrient absorption from digested food to endothelial cells that modulate nutrient delivery into tissues to gating of transport of nutrients at the plasma membrane of each individual cell. The passage of specific nutrients at each of these barriers can be regulated by endocytic membrane traffic in each tissue and cell type, such as by the uptake of specific nutrients by receptor-mediated or fluid-phase internalization or the regulation of access of permeases and other transport proteins to extracellular nutrients by their endocytic membrane traffic. Importantly, each of these phenomena is regulated by myriad signals that are derived from cellular and systemic metabolism, thus creating intricate and elegant feedback mechanisms that modulate nutrient delivery and utilization. In single-celled eukaryotes such as yeast, the regulation of nutrient uptake and utilization is also controlled by endocytic membrane traffic, and the control of this phenomenon by metabolic and stress signals may be even more responsive to the wider range of environmental conditions than those experienced by individual cells in a multicellular organism. Altogether, an intimate and long-standing relationship between endocytic membrane traffic and metabolism emerges. This set of reviews examines the profound relationship between endocytic membrane traffic and metabolism at multiple levels. Collectively, this work highlights the plasticity and versatility of the endocytic network and its ability to be modulated by signals derived from cellular and whole-body metabolism, which in turn allows the specific endocytic processes of many different cell types to regulate systemic metabolic homeostasis. The first review by Gilleron et al11 delineates the state of our understanding of how endocytic membrane traffic directs the uptake and utilization of specific nutrients in key metabolic target tissues, including liver, muscle and adipocytes. This review focuses on what has been gleaned from animal models and clinical studies, delineating how endocytic membrane traffic control of key nutrient transporters and receptors impacts whole-body physiology and how disruptions in this regulation contribute to diseases such as diabetes and liver disease. This review also examines how endosomal traffic in certain tissues critically gates the action of certain metabolic signals, focusing on how endocytic membrane traffic of key metabolic hormone receptors such as insulin and glucagon receptors may modulate their intracellular signaling and physiological outcome. The second review by Yazdani et al12 examines the mechanisms by which the transport of molecules such as glucose and metabolic hormones such as insulin throughout the body is controlled by endothelial cell barriers, which establishes multiple points of regulation prior to the arrival of these molecules to their target tissues and cells. This review first discusses how the gating of the transport of glucose from the bloodstream to key target tissues such as the brain or skeletal muscle is controlled by endothelial layers specialized for the metabolic role and requirements of each tissue. Furthermore, the transport of hormones and nutrient carriers from blood to peripheral tissues and from the latter to the lymphatic system is examined. This review highlights the importance of control of systemic metabolism by these endothelial barriers and how we understand endocytosis and endosomal traffic to contribute to this endothelial transport. In the third review by Rahmani et al,13 we examine the reciprocal relationship of how signals derived from cell metabolism impact endocytic membrane traffic, with emphasis on cell autonomous metabolic cues. Focusing largely on mammalian cells, this review delineates how sufficiency or limitations of specific nutrients, including glucose, ATP and amino acids, are sensed, such as by triggering changes in activity of signaling kinases such as AMP-activated protein kinase (AMPK) or mechanistic target of rapamycin (mTOR), which in turn regulate endocytic membrane traffic in a variety of tissues and cell types. In addition, this article examines how metabolic control of endocytic traffic can also be mediated by the availability of metabolites such as uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) produced by the hexosamine biosynthetic pathway, which serves as a key nutrient-sensitive substrate for post-translational modification of specific proteins that in turn gate endocytic traffic. The fourth review by Babst14 examines the metabolic control of amino acid transporters in yeast, focusing on the control of endocytosis of amino acid-polyamine-organocation (APC) transporters by the availability of amino acids and other nutrients. This review examines how intricate feedback and sensing systems operate to control the rate of cellular uptake of amino acids through modulation of transporter localization to eisosomes, distinct plasma membrane domains that may serve as storage pools for these transporters. In addition to direct sensing of amino acids by APC transporters, this review also discusses several metabolic and membrane stress signals that regulate eisosomes and gate APC transporter endocytic traffic, including AMPK and TOR, highlighting the conservation of the control of endocytic membrane traffic by these important metabolic sensors.

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