Endocytosis in the adaptation to cellular stress

Abstract

Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic regulation of select proteins conceivably can help to counteract adverse environmental conditions. In this review we summarize recent data regarding stress-induced changes in endocytosis and discuss how these changes might contribute to the cellular adaptation to stress in different systems. Future studies will be needed to uncover the underlying mechanisms in detail and to arrive at a coherent picture.

Keywords: cancer; clathrin-mediated endocytosis; hypoxia; mechanical stress; nutrient signaling; osmotic stress; oxidative stress.

Figure 1. FIGURE 1: Effects of stress conditions on Clathrin-mediated endocytosis.

Stress conditions can either promote (right side) or hamper (left side) endocytosis. Increased endocytosis, e.g. triggered by the stress-induced activation of the mitogen-activated protein kinase p38 that activates Rab5 by promoting the formation of GDI:Rab5 complexes, reduces the cell surface levels of transmembrane cargo proteins. This may, for example, restrict signaling from the plasma membrane or the transporter-mediated uptake of nutrients and/or enhance the endocytic uptake of specific protein-bound ligands. Conversely, downregulation of endocytosis will extend the residence time of signaling receptors and transporters at the cell surface, thereby promoting their activities (see text and other figures for details).

Figure 2. FIGURE 2: Regulation of amino acid transporter endocytosis by nutrient stress.

During energy sufficiency the arrestin-like adaptor Art1 recruits the ubiquitin ligase Rsp5 to the plasma membrane to induce the ubiquitination of the arginine transporter Can1. Subsequent endocytosis of Can1 limits amino acid uptake. This pathway is regulated by the central nutrient sensor mTORC1 which in its active state keeps the negative regulator of Art1, the kinase Npr1, inactive. During starvation mTORC1 is rendered inactive so that Npr1 can inhibit Art1 via phosphorylation. Consequently, Can1 is not ubiquitinated by Rsp5 and remains at the plasma membrane to increase arginine uptake (see section ”Endocytosis and nutrient signaling” for further details). CCV, clathrin-coated vesicle; EE, early endosome; RE, recycling endosome; LE, late endosome.

Figure 3. FIGURE 3: Regulation of glucose transporter endocytosis by nutrient stress.

Under conditions of abundant glucose the adaptor protein TXNIP promotes the endocytosis of GLUT1 to restrict glucose uptake. When glucose levels decline, AMPK activation triggers the degradation of TXNIP, thereby downregulating GLUT1 endocytosis to promote glucose uptake (see section ”Glucose and energy deprivation” for further details).

Figure 4. FIGURE 4: Regulation of ion transporter endocytosis by osmotic stress.

Under iso-osmotic conditions NHE7 is continuously endocytosed via CME, thereby limiting its transport activity at the cell surface. Upon hyperosmotic conditions, endocytosis of NHE7 is downregulated resulting in elevated NHE7 surface levels. Increased NHE7 activity at the plasma membrane elevates Na⁺ influx, which via the Na⁺/Ca²⁺ exchanger NCX1 leads to increased intracellular Ca²⁺ levels and the Ca²⁺/Calcineurin-mediated dephosphorylation of the transcription factor TFEB to induce lysosomal and autophagy gene expression. The ensuing increased cellular degradative capacity is beneficial for counteracting protein aggregation caused by hyperosmotic conditions (see section ”Osmotic stress” for further details).

Figure 5. FIGURE 5: Regulation of endocytosis by mechanical stress.

Proximal tubule cells are tasked with the uptake of proteins and other molecules from the glomerular filtrate. Increased fluid shear stress bends primary cilia, thereby triggering Ca²⁺ influx that is further amplified intracellularly. Via activation of Calmodulin this change induces Cdc42-mediated actin polymerization and enhanced endocytosis to prevent proteinuria (see section ”Mechanical stress” for further details).

Figure 6. FIGURE 6: Regulation of endocytosis by oxygen stress.

Under adequate oxygen supply there is limited endocytosis of the Na⁺/K⁺-ATPase, which is needed at the plasma membrane to build up the ion gradient that supports alveolar fluid clearance. When oxygen levels drop, the endocytosis of Na⁺/K⁺-ATPase is promoted to preserve energy. Hypoxia-induced ROS via an increase in Ca²⁺ lead to the activation of CAMKK-β which activates AMPK and PKC-ζ. PKC-γ phosphorylates sites on AP-2 and the Na⁺/K⁺-ATPase to boost Na⁺/K⁺-ATPase endocytosis. During prolonged hypoxia, the HIF pathway triggers the ubiquitination and degradation of PKC-ζ by elevating the expression of the E3 ubiquitin ligase HOIL-1L. In this way cells balance energy preservation and alveolar fluid clearance for cellular and organismal survival (see section ”Hypoxia – O₂ stress” for further details).