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

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 alpha (CNTFR alpha) and is a prerequisite for signaling through the gp130/leukemia inhibitory factor receptor beta (LIFR beta) 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 CNTFR alpha and sorLA, is a key player in CLC and CNTFR alpha signaling and turnover. The site for CNTFR alpha enables CLF-1 to promote CLC:CNTFR alpha complex formation and signaling. The second site establishes a link between the endocytic receptor sorLA and the tripartite CLC:CLF-1:CNTFR alpha complex and allows sorLato downregulate the CNTFR alpha pool in stimulated cells. Finally, sorLamay bind and concentrate the tripartite soluble CLC:CLF-1:CNTFR alpha complex on cell membranes and thus facilitate its signaling through gp130/LIFR beta.