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Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor

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Abstract

Although clinically useful for the treatment of various diseases, type I interferons (IFNs) have been implicated as causative factors of a number of neuroinflammatory disorders characterized by neuronal damage and altered CNS functions. As neurotrophin 3 (NT3) plays a critical role in neuroprotection, we examined the effects of IFN-β on the signalling and functional activity of the NT3/TrkC system. We found that prolonged exposure of differentiated human SH-SY5Y neuroblastoma cells to IFN-β impaired the ability of NT3 to induce transphosphorylation of the full-length TrkC receptor (TrkC-FL) and the phosphorylation of downstream signalling molecules, including PLCγ1, Akt, GSK-3β and ERK1/2. NT3 was effective in protecting the cells against apoptosis triggered by serum withdrawal or thapsigargin but not IFN-β. Prolonged exposure to the cytokine had little effects on TrkC-FL levels but markedly enhanced the messenger RNA (mRNA) and protein levels of the truncated isoform TrkC-T1, a dominant-negative receptor that inhibits TrkC-FL activity. Cell depletion of TrkC-T1 by small interfering RNA (siRNA) treatment enhanced NT3 signalling through TrkC-FL and allowed the neurotrophin to counteract IFN-β-induced apoptosis. Furthermore, the upregulation of TrkC-T1 by IFN-β was associated with the inhibition of NT3-induced recruitment of the scaffold protein tamalin to TrkC-T1 and tamalin tyrosine phosphorylation. These data indicate that IFN-β exerts a negative control on NT3 pro-survival signalling through a novel mechanism involving the upregulation of TrkC-T1.

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Acknowledgments

This study was supported by a grant from Regione Autonoma della Sardegna, Italy. L.R. n.7/2007-CRP 10810/2012.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Simona Dedoni, Maria C. Olianas & Pierluigi Onali

  2. Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Angela Ingianni

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  1. Simona Dedoni
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  2. Maria C. Olianas
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  4. Pierluigi Onali
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Correspondence to Pierluigi Onali.

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Dedoni, S., Olianas, M.C., Ingianni, A. et al. Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor. Mol Neurobiol 54, 1825–1843 (2017). https://doi.org/10.1007/s12035-016-9789-2

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