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Reciprocal Regulation of Endocytosis and Metabolism Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Reciprocal Regulation of Endocytosis and Metabolism Costin N. Antonescu1, Timothy E. McGraw2, and Amira Klip3 1Department of Chemistry and Biology, Ryerson University, Toronto, Ontario M5B 2K3, Canada 2Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10065 3Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada Correspondence: [email protected]; [email protected] The cellular uptake of many nutrients and micronutrients governs both their cellular avail- ability and their systemic homeostasis. The cellular rate of nutrient or ion uptake (e.g., glucose, Fe3þ,Kþ) or efflux (e.g., Naþ) is governed by a complement of membrane transport- ers 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. nteractions between the cell and its environ- by the balance of its endocytosis and its recy- Iment obligatorily involve events at the plasma cling back to the cell surface from endosomes membrane. Cell-surface proteins mediate nutri- and other intracellular compartments (Fig. 1). ent uptake, product release, and the sensing of Changes in the kinetics of membrane protein environmental changes, including signals from traffic acutely affect the levels of individual pro- other cells. Appropriate sensing and response to teins at the cell surface and thereby impact how extracellular cues is essential for the individual cells intake nutrients, sense the environment, cell’s survival and for the coordinated cellular and respond to external cues. behavior in multicellular organisms. Accord- Selective molecular mechanisms trigger ingly, maintenance and dynamics of membrane traffic of plasma membrane proteins through proteins are fundamental mechanisms of cellu- endomembranes. Among them, ubiquitination lar homeostasis and survival. and phosphorylation stand out as they can di- Most plasma membrane proteins are in de- rectly target the cargo proteins. Ubiquitination fined equilibria with intracellular endosomal is the covalent attachment of the 76-amino acid compartments, such that the amount of a given polypeptide ubiquitin to the 1-amino group protein at the plasma membrane is determined of specific lysine residues (reviewed by Miranda Editors: Sandra L. Schmid, Alexander Sorkin, and Marino Zerial Additional Perspectives on Endocytosis available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016964 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016964 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press C.N. Antonescu et al. Nutrients and hormones Cell surface Transporters and receptors Exocytosis/ Endocytosis recycling Endosomes 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. and Sorkin 2007; and see also Piper et al. 2014). affinity iron chelating glycoprotein made by the Ubiquitination of cell-surface proteins is the liver (Gkouvatsos et al. 2012). Endocytosis of principal mechanism of control of endocytosis diferricTfistheprincipalmechanismforcellular in yeast (MacGurn et al. 2012), whereas in mam- Fe3þ uptake. Transferrin receptor 1 (TfR1), a mals, additional molecular mechanisms regu- homodimeric type II transmembrane protein 3þ late the endocytosis of cell-surface proteins, in- that binds Tf-Fe2 with nanomolar affinity, is cluding alterations in conformation that impact the primary receptor mediating cellular uptake 3þ interaction with other proteins, and as men- (Fig. 2). The Tf-Fe2 :TfR1 complex is internal- tioned, phosphorylation. Each of these modifi- ized by clathrin-mediated endocytosis (CME) cations can either enhance or reduce the rates (Dautry-Varsat et al. 1983; Klausner et al. internalization, recycling, or degradation of spe- 1983). At the acidic luminal pH of endosomes cific proteins, highlighting the complexity of the (pH 5.5–6.0), Fe3þ is released from Tf, reduced, regulation of endomembrane traffic. The intri- and transported to the cytosol. Apo-Tf (iron- cate mechanisms that underlie the reciprocal free) has high affinity for TfR1 at acidic pH and regulation of endocytosis and metabolism are therefore remains bound to TfR1 in endosomes. beginning to be understood. Here we discuss The Apo-Tf:TfR1 complex returns to the plasma the endocytosis mechanisms in the regulation membrane through mildly acidic, endocytic re- of cellular intake or efflux of iron, cholesterol, cycling compartments. Apo-Tf has an approxi- Naþ, and glucose, and in the regulation of re- mate 500-foldloweraffinityforTfR1atneutral ceptor signaling relevant to metabolism. pH and it is therefore released from TfR1 follow- ing the fusion of recycling vesicles with the plas- ENDOCYTOSIS IS REQUIRED FOR THE ma membrane (where it is exposed to extracel- UPTAKE OF CIRCULATING NUTRIENT lular milieu of pH 7.4). The released apo-Tf is 3þ CARRIERS free to bind Fe in the blood and mediate addi- tional Fe3þ delivery upon binding to TfR1. Regulation of Iron Homeostasis by TfR1 constitutively cycles between the plas- Transferrin Internalization ma membrane and endosomes (Watts 1985; Gi- Ferric iron (Fe3þ) is an essential nutrient that is rone`s and Davis 1989). Internalization of TfR1 carried in the blood by transferrin (Tf ), a high- is mediated by a cytoplasmic YTRF-based motif 2 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016964 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Endocytosis and Metabolism Fe3+ Cell surface CME 3+ Fe Recycling endosome Tfn receptor Early endosome Holo-Tf Apo-Tf 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. associating with the m-subunit of the AP2 rects the receptor to degradation in lysosomes clathrin adaptin complex (Jing et al. 1990; (Tachiyama et al. 2011). Together, these mecha- McGraw and Maxfield 1990; Ohno et al. 1995; nisms control less Fe3þ accumulation upon ele- Owen and Evans 1998). Mutations in YTRF re- vated cellular Fe3þ. ducetheinternalizationrateconstantoftheTfR1 Whole body iron homeostasis is achieved and correspondingly reduce the rate of Fe3þ in- by the balance of TfR1-mediated uptake from tracellularaccumulation, revealingthatinternal- duodenal enterocytes (dietary iron) and mac- ization of the TfR1 is rate limiting for Fe3þ up- rophages (iron recycled from erythrocytes) to take (McGrawand Maxfield 1990; Pytowski et al. the plasma via the ferroportin (FPN)-depen- 1995). dent iron transport (Donovan et al. 2005). Although both constitutive endocytosis and The amount of FPN at the surface of these cells recycling of TfR1 are key elements controlling determines the rate of iron export to plasma. cellular Fe3þ accumulation by maintaining the Hepcidin, a liver-produced, 27-amino acid hor- appropriate steady-state level of TfR1 at the plas- mone, controls iron transport from enterocytes ma membrane, the regulation of TfR1 traffic and macrophages into the plasma by inhibiting (endocytosis and/or recycling) is not a major FPN. Hepcidin binds FPN inducing its ubiqui- mode for the modulation of cellular of Fe3þ ac- tylation-dependent endocytosis (Nemeth et al. cumulation. Rather, regulation of iron accumu- 2004; Qiao et al. 2012). Internalized FPN is tar- lation is controlled at the level of TfR1 mRNA geted to lysosomes for degradation. Although stability (Rouault 2006). In low Fe3þ conditions the molecular details of the ubiquitin-based there is increased TfR1 mRNA stability and FPN internalization and down-regulation have elevated total TfR1 protein that brings about not been fullyelucidated, it is clear that hepcidin a steady-state increase of TfR1 at the plasma regulation of FPN endocytosis is essential for membrane and augmented capacity
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