Reciprocal regulation of endocytosis and metabolism

Abstract

The cellular uptake of many nutrients and micronutrients governs both their cellular availability and their systemic homeostasis. The cellular rate of nutrient or ion uptake (e.g., glucose, Fe(3+), K(+)) or efflux (e.g., Na(+)) is governed by a complement of membrane transporters and receptors that show dynamic localization at both the plasma membrane and defined intracellular membrane compartments. Regulation of the rate and mechanism of endocytosis controls the amounts of these proteins on the cell surface, which in many cases determines nutrient uptake or secretion. Moreover, the metabolic action of diverse hormones is initiated upon binding to surface receptors that then undergo regulated endocytosis and show distinct signaling patterns once internalized. Here, we examine how the endocytosis of nutrient transporters and carriers as well as signaling receptors governs cellular metabolism and thereby systemic (whole-body) metabolite homeostasis.

Figure 1.

Dynamic regulation of the cell-surface content of membrane proteins. Integral membrane proteins found at the cell surface are dynamically localized to the plasma membrane. The amount of any of these proteins at the cell surface is the result of the balance of exocytosis or recycling of vesicles containing that protein from intracellular membrane compartments and the endocytosis of the protein from the cell surface. Regulation of either the rate of exocytosis or endocytosis results in alteration of the cell-surface content of a given protein.

Figure 2.

The uptake of iron through endocytosis and recycling of transferrin. Iron-bound transferrin (holo-Tf) binds to the transferrin receptor (TfR) at the cell surface. TfR constitutively internalizes via clathrin-mediated endocytosis. Arrival of the Tf/TfR complex to the acidic environment of endosomes results in dissociation of iron from Tf. This is followed by recycling of the apo-Tf/TfR complex to the cell surface, where apo-Tf dissociates from TfR. The iron is thereby retained intracellularly, and Tf and TfR are able to participate in additional rounds of iron uptake.

Figure 3.

Control of glucose uptake by regulation of GLUT1 and GLUT4 endocytosis. Glucose transport from the extracellular milieu to the cytoplasm occurs selectively by glucose transporters (GLUTs) present at the cell surface. GLUT4 endocytosis occurs through both clathrin-mediated (CME) as well as clathrin-independent (CIE) endocytosis. The cell-surface content, and hence the rate of glucose uptake by GLUT1 and GLUT4, is regulated by alterations in the endocytosis of these glucose transporters, as well as the rates of recycling. Moreover, GLUT1 and GLUT4 undergo distinct intracellular sorting, with ∼50% of GLUT4 residing in a specialized storage compartment. Shown are some of the stimuli and intracellular signals that reduce the endocytosis of GLUT1 and GLUT4 or increase transporter recycling and thereby increase the rate of cellular glucose uptake. Also shown are the insulin-responsive aminopeptidase (IRAP) and VAMP2, which are enriched in the GLUT4 storage compartment and the transferrin receptor (Tfn rec.), which is not, and is instead found largely in recycling endosomes.

Figure 4.

The internalization and recycling of the insulin receptor. Insulin binding to its receptor (IR) results in rapid internalization of the insulin-IR complex via either clathrin-mediated endocytosis (CME) or clathrin-independent endocytosis (CIE). On arrival within the acidic environment of endosomes, insulin dissociates from the IR. Insulin is degraded by insulin-degrading enzymes (IDE), whereas the IR undergoes efficient recycling to the PM. In contrast to other tissues, in endothelial cells insulin predominantly undergoes transcytosis without degradation. By comparison, the binding of epidermal growth factor (EGF) to its receptor (EGFR) results in rapid internalization leading largely to lysosomal degradation of the EGF-EGFR complex.