A Bcl-xL–Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis

Abstract

Following exocytosis, the rate of recovery of neurotransmitter release is determined by vesicle retrieval from the plasma membrane and by recruitment of vesicles from reserve pools within the synapse, the latter of which is dependent on mitochondrial ATP. The Bcl-2 family protein Bcl-xL, in addition to its role in cell death, regulates neurotransmitter release and recovery in part by increasing ATP availability from mitochondria. We now find, however, that, Bcl-xL directly regulates endocytotic vesicle retrieval in hippocampal neurons through protein/protein interaction with components of the clathrin complex. Our evidence suggests that, during synaptic stimulation, Bcl-xL translocates to clathrin-coated pits in a calmodulin-dependent manner and forms a complex of proteins with the GTPase Drp1, Mff and clathrin. Depletion of Drp1 produces misformed endocytotic vesicles. Mutagenesis studies suggest that formation of the Bcl-xL-Drp1 complex is necessary for the enhanced rate of vesicle endocytosis produced by Bcl-xL, thus providing a mechanism for presynaptic plasticity.

Caspase-3–dependent cleavage of Bcl-xL in the stroma exosomes is required for their uptake by hematological malignant cells

“…In accordance with the previously mentioned findings, the cleaved Bcl-xL activity can be inhibited by ABT737 in a similar manner as we observed in our studies. 23 One interesting observation from our studies was that the selected cell lines have differential propensity to uptake exosomes. RPMI 8226 cells uptake exosomes at much higher rates compared with OPM2.…”

“…In 2 different publications, it has been shown that Bcl-xL plays a role in membrane dynamics and synaptic vesicle uptake. 23,24 Li et al showed that the synaptic vesicle uptake is mediated by the interaction of Bcl-xL with Drp-1. 23 It would be interesting to investigate whether the same molecular complex mediates the uptake and endocytosis of exosomes by recipient cells.…”

“…21,22 Furthermore, an additional role was added to the Bcl-xL repertoire as a regulator of synaptic vesicle membrane dynamics and endocytosis through its interaction with Drp-1. 23,24 Having observed that Bcl-xL is located at the outer leaflet of the L88 exosomes, we examined whether it may play a role in the intracellular uptake by the recipient MM cell lines, RPMI 8226 and OPM2. Labeling of L88-derived exosomes with the lipophilic dye followed by uptake studies demonstrated that these vesicles are readily internalized by OPM2 and RPMI 8226 cells in a time-dependent manner ( Figure 3A-B).…”

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells

“…BCL-x L is an antiapoptotic protein with a role in the regulation of membrane dynamics and endocytosis. 27 DOCK8, a member of the evolutionarily conserved DOCK family proteins, 28 was shown to bind to nucleotide-free CDC42 to mediate the GTP-GDP exchange reaction. Thereby, CDC42 is spatially activated at the plasma membrane, 29 where it plays a crucial role in apical differentiation and BBM formation.…”

Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress

“…Because Drp1 physically interacts with Bcl-xL in neurons 24 and Bcl-xL inhibits autophagy through its binding to Beclin1, we investigated the involvement of Bcl-xL in the suppression of autophagy by Drp1. Using coimmunoprecipitation assays, we confirmed that Drp1 physically interacts with Bcl-2 and BclxL in cardiomyocytes in the presence of Drp1 overexpression (Online Figure IIIA).…”