Cytokine-Like Factor 1, an Essential Facilitator of Cardiotrophin-Like Cytokine:Ciliary Neurotrophic Factor Receptor α Signaling and sorLA-Mediated Turnover

• Published in: Molecular and cellular biology 2016-04, Vol.36 (8), p.1272-1286
• Main Authors: Larsen, Jakob Vejby, Kristensen, Anders Mejer, Pallesen, Lone Tjener, Bauer, Johannes, Vægter, Christian Bjerggaard, Nielsen, Morten Schallburg, Madsen, Peder, Petersen, Claus Munck
• Format: Article
• Language: English
• Subjects: Ciliary Neurotrophic Factor Receptor alpha Subunit - metabolism; Cytokines - metabolism; HEK293 Cells; Humans; LDL-Receptor Related Proteins - metabolism; Membrane Transport Proteins - metabolism; Protein Binding; Receptors, Cytokine - metabolism; Signal Transduction; Spotlight
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00917-15

Cardiotrophin-like cytokine:cytokine-like factor-1 (CLC:CLF-1) is a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development. Mice lacking CLC:CLF-1 die soon after birth due to a suckling defect and show reduced numbers of motor neurons. Humans carrying mutations in CLC:CLF-1 develop similar disorders, known as Sohar-Crisponi or cold-induced sweating syndrome, and have a high risk of early death. It is well known that CLC binds the ciliary neurotrophic factor receptor α (CNTFRα) and is a prerequisite for signaling through the gp130/leukemia inhibitory factor receptor β (LIFRβ) heterodimer, whereas CLF-1 serves to promote the cellular release of CLC. However, the precise role of CLF-1 is unclear. Here, we report that CLF-1, based on its binding site for CLC and on two additional and independent sites for CNTFRα and sorLA, is a key player in CLC and CNTFRα signaling and turnover. The site for CNTFRα enables CLF-1 to promote CLC:CNTFRα complex formation and signaling. The second site establishes a link between the endocytic receptor sorLA and the tripartite CLC:CLF-1:CNTFRα complex and allows sorLA to downregulate the CNTFRα pool in stimulated cells. Finally, sorLA may bind and concentrate the tripartite soluble CLC:CLF-1:CNTFRα complex on cell membranes and thus facilitate its signaling through gp130/LIFRβ.