Sortilin Facilitates Signaling of Ciliary Neurotrophic Factor and Related Helical Type 1 Cytokines Targeting the gp130/Leukemia Inhibitory Factor Receptor β Heterodimer

Abstract

Sortilin is a member of the Vps10p domain family of neuropeptide and neurotrophin binding neuronal receptors. The family members interact with and partly share a variety of ligands and partake in intracellular sorting and protein transport as well as in transmembrane signal transduction. Thus, sortilin mediates the transport of both neurotensin and nerve growth factor and interacts with their respective receptors to facilitate ligand-induced signaling. Here we report that ciliary neurotrophic factor (CNTF), and related ligands targeting the established CNTF receptor ␣, binds to sortilin with high affinity. We find that sortilin may have at least two functions: one is to provide rapid endocytosis and the removal of CNTF, something which is not provided by CNTF receptor ␣, and the other is to facilitate CNTF signaling through the gp130/leukemia inhibitory factor (LIF) receptor ␤ heterodimeric complex. Interestingly, the latter function is independent of both the CNTF receptor ␣ and ligand binding to sortilin but appears to implicate a direct interaction with LIF receptor ␤. Thus, sortilin facilitates the signaling of all helical type 1 cytokines, which engage the gp130/LIF receptor ␤ complex.

Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies

“…3) [27]. In vitro studies demonstrated that sortilin could substitute for CNTFRa to facilitate the recruitment and activation of the signaling chains gp130 and LIFRb [27].…”

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

“…It is a member of the Vps10p domain receptor family, characterized by a 10-bladed β-propeller that forms a cavity for binding of soluble ligands and a C-terminal cytoplasmic tail that contains sorting motifs responsible for subcellular distribution of the receptors (8)(9)(10). Sortilin exerts diverse cellular functions including intracellular sorting of proteins, such as acid sphingomyelinase, apolipoprotein B100 (apoB100), and PCSK9, as well as engaging in signaling as a coreceptor in cell surface receptor complexes (5)(6)(7)(11)(12)(13). Given the broad functional repertoire of sortilin, we hypothesized that it may affect atherogenesis beyond regulating plasma cholesterol levels.…”

σ1B-adaptin sorts sortilin in adipose tissue regulating adipogenesis

“…Sortilin binds to soluble ligands and forms heterodimeric complexes with other receptors and pro-hormones with transmembrane domains. Complex formation can promote anterograde as well as retrograde transport of these receptors and, thus, alter hormone signalling, but complex formation can also alter receptor-ligand specificities and, thus, the activity of signalling pathways (Hermey, 2009;Larsen et al, 2010;Willnow et al, 2008). We found that AP-1-dependent sortilin sorting is mediated by two motifs, one of which mediates sorting by AP-1 complexes containing s1A or s1B (AP-1-s1A or AP-1-s1B complexes) and the second of which binds specifically to s1B.…”