EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons

Scientific Reports
Katja BurkCamin Dean

Abstract

The sorting of activated receptors into distinct endosomal compartments is essential to activate specific signaling cascades and cellular events including growth and survival. However, the proteins involved in this sorting are not well understood. We discovered a novel role of EndophilinAs in sorting of activated BDNF-TrkB receptors into late endosomal compartments. Mice lacking all three EndophilinAs accumulate Rab7-positive late endosomes. Moreover, EndophilinAs are differentially localized to, co-traffic with, and tubulate, distinct endosomal compartments: In response to BDNF, EndophilinA2 is recruited to both early and late endosomes, EndophilinA3 is recruited to Lamp1-positive late endosomes, and co-trafficks with Rab5 and Rab7 in both the presence and absence of BDNF, while EndophilinA1 colocalizes at lower levels with endosomes. The absence of all three EndophilinAs caused TrkB to accumulate in EEA1 and Rab7-positive endosomes, and impaired BDNF-TrkB-dependent survival signaling cascades. In addition, EndophilinA triple knockout neurons exhibited increased cell death which could not be rescued by exogenous BDNF, in a neurotrophin-dependent survival assay. Thus, EndophilinAs differentially regulate activated receptor sort...Continue Reading

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Citations

Feb 6, 2019·Acta Neuropathologica·Katja Burk, R Jeroen Pasterkamp
Jan 9, 2019·Frontiers in Cellular Neuroscience·Guillermo Moya-AlvaradoFrancisca C Bronfman
Jun 13, 2018·Frontiers in Molecular Neuroscience·Yanrui YangJia-Jia Liu
Feb 23, 2020·Journal of Cell Science·Marta I BudzinskaGiampietro Schiavo
Sep 22, 2020·Brain Structure & Function·Shoko TakemuraAkio Wanaka
Dec 2, 2020·Journal of Neurochemistry·Annemiek A van BerkelMatthijs Verhage
Sep 30, 2020·Progress in Neurobiology·R J Pasterkamp, K Burk

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Methods Mentioned

BETA
GTPases
co-immunoprecipitation
pull down
genotyping
PCR
dissection
transfection

Software Mentioned

1000
ImageJ
Metamorph
ND

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