Endocytic regulation of cytokine receptor signaling

Abstract

Signaling of plasma membrane receptors can be regulated by endocytosis at different levels, including receptor internalization, endocytic sorting towards degradation or recycling, and using endosomes as mobile signaling platforms. Increasing number of reports underscore the importance of endocytic mechanisms for signaling of cytokine receptors. In this short review we present both consistent and conflicting data regarding endocytosis and its role in signaling of receptors from the tumor necrosis factor receptor superfamily (TNFRSF) and those for interleukins (ILRs) and interferons (IFNRs). These receptors can be internalized through various endocytic routes and most of them are able to activate downstream pathways from endosomal compartments. Moreover, some of the cytokine receptors clearly require endocytosis for proper signal transduction. Still, the data describing internalization mechanisms and fate of cytokine receptors are often fragmentary and barely address the relation between their endocytosis and signaling. In the light of growing knowledge regarding different mechanisms of endocytosis, extending it to the regulation of cytokine receptor signaling may improve our understanding of the complex and pleiotropic functions of these molecules.

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

“…In vivo , it is more likely that scavenging microglia encounter an infected astrocyte or neuron and become activated by signals released from these more permissive cell types. Activation of bystander microglia is strongly linked with neuroinflammation in a number of neurodegenerative diseases, and we hypothesized that it could significantly contribute to the pro-inflammatory cytokine load during VEEV infection [45,46]. Our investigation revealed that bystander microglia exposed to overlays from infected astrocytes produce significantly more IL-1α, IL-1β, IL-6, and IL-8 as compared to the directly infected cells.…”

Cytokine Receptor Endocytosis: New Kinase Activity-Dependent and -Independent Roles of PI3K

“…Receptors are internalized from the plasma membrane into endocytic compartments, collectively called “endosomes” by endocytosis (8), which has long been recognized as a major mechanism to attenuate receptor signaling (14, 15). Constitutive (non-cytokine-induced) endocytosis regulates the number of receptors available on the cell surface to bind cytokines.…”

“…Both CME and CIE are involved in endocytosis of cytokine receptors (15, 19, 38–40). CME mediates endocytosis of gp130, the shared receptor for IL6 family cytokines, and receptors for prolactin, thrombopoietin, erythropoietin, interferon, IL5 (IL5Rα), IL7 (IL7Rα), and IL36 (18, 39, 41–48).…”

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

“…A common feature to all cytokine systems is that upon ligand stimulation cytokine-receptor complexes traffic to intracellular compartments, where they are often degraded, contributing to switching off the response (Becker et al, 2010;Bulut et al, 2011;Claudinon et al, 2007;German et al, 2011;Keeler et al, 2007;Shah et al, 2006). However, a complex positive regulatory role of endocytosis in cytokine signaling has emerged (Becker et al, 2010;Cendrowski et al, 2016;Fallon and Lauffenburger, 2000;Marchetti et al, 2006;Sarkar et al, 2002). Several studies recently suggested a novel role for the endosomal compartment in stabilizing cytokine receptor dimers by enhancing local receptor concentrations (Gandhi et al, 2014;Moraga et al, 2015a), thus contributing to signaling fitness even at low complex stabilities.…”