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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.
Highlights
Endophilins were initially discovered through a screen for SH3 domain-containing proteins in a mouse embryonic cDNA library
To determine if EndophilinAs have a role in endosomal sorting, we first investigated if early (EEA1-positive) or late (Rab7-positive) endosomes were altered in EndophilinA1-/, A2-/- A3-/- triple knockout mice ( TKO)[6] compared to control wildtype mice using immunocytochemistry to label endogenous levels of EEA1 and Rab[7] in hippocampal neurons (Fig. 1A)
Since we found no significant increase in the localization of EndophilinA1 to endosomal compartments in the presence and absence of BDNF, we concluded a minor involvement of EndophilinA1 in potential endosomal sorting
Summary
Endophilins were initially discovered through a screen for SH3 domain-containing proteins in a mouse embryonic cDNA library. The sorting of activated receptors to different endosomal compartments is accomplished by the retromer complex, which sorts endocytosed receptors into tubular microdomains of early endosomes formed by the sorting nexins[15] These tubules are pinched off at the very tip by dynamin to form vesicles which are routed via endosomal markers for recycling, long-range trafficking, or degradation[16]. We hypothesized that EndophilinAs - which contain BAR domains and SH3 domains - may be present on endosomal compartments to promote the sorting of activated receptors, in addition to their well-known role in endocytosis from the plasma membrane. We discovered a novel function of EndophilinAs, in addition to their well-described role in synaptic vesicle and receptor endocytosis: EndophilinAs regulate endosomal sorting of activated TrkB receptors and subsequent signaling cascades to promote cell survival
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