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 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.

PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

“…Interestingly, PTPN23 binds endophilin A1 (Ichioka et al, 2007), which is involved in the endocytic sorting of TrkB (Burk et al, 2017). Endophilin knockdown leads to accumulation of TrkB in EEA1-and Rab7-positive endosomes (Burk et al, 2017), which aligns well with our results (Fig. 7).…”

“…Although further work is necessary to fully characterise the PTPN23-KD phenotype described here, the role of PTPN23 in intracellular cargo sorting is somewhat easier to interpret than how BICD1 performs this function, primarily due to the extensive literature focussed on the characterisation of PTPN23 in EGFR dynamics (Woodman, 2016;Gahloth et al, 2016Gahloth et al, , 2017Tabernero and Woodman, 2018). Interestingly, PTPN23 binds endophilin A1 (Ichioka et al, 2007), which is involved in the endocytic sorting of TrkB (Burk et al, 2017). Endophilin knockdown leads to accumulation of TrkB in EEA1-and Rab7-positive endosomes (Burk et al, 2017), which aligns well with our results (Fig.…”

Sensory Axon Growth Requires Spatiotemporal Integration of CaSR and TrkB Signaling

“…6C,D). The routing of activated TrkB into Rab7 endosomes has been reported by other groups (Kuruvilla et al, 2004;Deinhardt et al, 2006;Burk et al, 2017b). Further, Trk receptors start their downstream signaling from the endosomal compartment to which they localize (Wu et al, 2001;Kuruvilla et al, 2004;Saxena et al, 2005;Zhou et al, 2012;Barford et al, 2017).…”

Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2

“…Moreover, BDNF-induced survival signaling in hippocampal neurons has been shown to be regulated by Endophilin-A, that is involved in endosomal sorting of active TRKB receptors (39) . Evidence suggests that the maintenance of long-term potentiation in hippocampal slices depends on the recycling and re-secretion of BDNF, thus, emphasizing the necessity of TRKB receptor recycling back to the cell surface (55) .…”