EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons
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...
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2017-05-01
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Online Access: | https://doi.org/10.1038/s41598-017-02202-4 |
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doaj-5db9c009a4ee437b86f567fcdc9739042020-12-08T01:17:12ZengNature Publishing GroupScientific Reports2045-23222017-05-017111910.1038/s41598-017-02202-4EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neuronsKatja Burk0John D. Murdoch1Siona Freytag2Melanie Koenig3Vinita Bharat4Ronja Markworth5Susanne Burkhardt6Andre Fischer7Camin Dean8European Neuroscience Institute, ENI-GEuropean Neuroscience Institute, ENI-GEuropean Neuroscience Institute, ENI-GEuropean Neuroscience Institute, ENI-GEuropean Neuroscience Institute, ENI-GEuropean Neuroscience Institute, ENI-GGerman Center for Neurodegenerative Diseases (DZNE), University Medical Center GoettingenGerman Center for Neurodegenerative Diseases (DZNE), University Medical Center GoettingenEuropean Neuroscience Institute, ENI-GAbstract 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 sorting via distinct endosomal compartments to promote BDNF-dependent cell survival.https://doi.org/10.1038/s41598-017-02202-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katja Burk John D. Murdoch Siona Freytag Melanie Koenig Vinita Bharat Ronja Markworth Susanne Burkhardt Andre Fischer Camin Dean |
spellingShingle |
Katja Burk John D. Murdoch Siona Freytag Melanie Koenig Vinita Bharat Ronja Markworth Susanne Burkhardt Andre Fischer Camin Dean EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons Scientific Reports |
author_facet |
Katja Burk John D. Murdoch Siona Freytag Melanie Koenig Vinita Bharat Ronja Markworth Susanne Burkhardt Andre Fischer Camin Dean |
author_sort |
Katja Burk |
title |
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons |
title_short |
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons |
title_full |
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons |
title_fullStr |
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons |
title_full_unstemmed |
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons |
title_sort |
endophilinas regulate endosomal sorting of bdnf-trkb to mediate survival signaling in hippocampal neurons |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-05-01 |
description |
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 sorting via distinct endosomal compartments to promote BDNF-dependent cell survival. |
url |
https://doi.org/10.1038/s41598-017-02202-4 |
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