Journal
MOLECULAR NEURODEGENERATION
Volume 10, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13024-015-0065-0
Keywords
Beclin 1; VPS34; Retromer; TGF-beta; ALK5; Protein sorting; Receptor recycling; Neurodegeneration
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Funding
- National Institutes of Health Institute on Aging [R01 AG030144]
- National Institutes of Health Institute of Neurological Disorders and Stroke Ruth L. Kirschstein NRSA predoctoral fellowship [1F31NS078865]
- [BX001319]
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Background: Beclin 1 is a key regulator of multiple trafficking pathways, including autophagy and receptor recycling in yeast and microglia. Decreased beclin 1 levels in the CNS result in neurodegeneration, an effect attributed to impaired autophagy. However, neurons also rely heavily on trophic factors, and signaling through these pathways requires the proper trafficking of trophic factor receptors. Results: We discovered that beclin 1 regulates signaling through the neuroprotective TGF-beta pathway. Beclin 1 is required for recycling of the type I TGF-beta receptor ALK5. We show that beclin 1 recruits the retromer to ALK5 and facilitates its localization to Rab11(+) endosomes. Decreased levels of beclin 1, or its binding partners VPS34 and UVRAG, impair TGF-beta signaling. Conclusions: These findings identify beclin 1 as a positive regulator of a trophic signaling pathway via receptor recycling, and suggest that neuronal death induced by decreased beclin 1 levels may also be due to impaired trophic factor signaling.
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