Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation

Abstract

Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. Here, we characterize a critical step in this process: axonal transport of ESCRT-0 component Hrs, necessary for sorting proteins into the ESCRT pathway and recruiting downstream ESCRT machinery to catalyze multivesicular body (MVB) formation. We find that neuronal activity stimulates the formation of presynaptic endosomes and MVBs, as well as the motility of Hrs+ vesicles in axons and their delivery to SV pools. Hrs+ vesicles co-transport ESCRT-0 component STAM1 and comprise a subset of Rab5+ vesicles, likely representing pro-degradative early endosomes. Furthermore, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of Hrs to SV pools and the degradation of SV membrane proteins. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV membrane proteins.

Activity-dependent synthesis of Emerin gates neuronal plasticity by regulating proteostasis

“…Alterations in the newly-synthesized proteome can be influenced not only by transcriptomic changes [21][22][23][24] but also by multiple layers of post-transcriptional regulation of protein synthesis [25][26][27][28][29], trafficking [30,31] and degradation [32,33]. Consequently, the nascent proteome in the brain of intact animals is highly dynamic over time after exposure to external stimuli.…”

“…Changes in the proteome can be driven by gene transcription [22][23][24], as well as a myriad of transcription-independent processes, giving rise to multiple layers of spatial and temporal complexity of the proteome [25]. These processes, falling under the umbrella of proteostasis, include translational control by translational factors [26], local protein synthesis from readily available mRNAs [27], RNA-binding proteins buffering the translation of target mRNAs [28,29], protein trafficking [30,31] and proteosome-dependent degradation [32,33].…”

“…Changes in the proteome can be driven by gene transcription [22–24], as well as a myriad of transcription-independent processes, giving rise to multiple layers of spatial and temporal complexity of the proteome [25]. These processes, falling under the umbrella of proteostasis, include translational control by translational factors [26], local protein synthesis from readily available mRNAs [27], RNA-binding proteins buffering the translation of target mRNAs [28, 29], protein trafficking [30, 31] and proteosome-dependent degradation [32, 33]. Proteostasis is a crucial component for neuronal function and plasticity in both health and disease [34–36], however, it is not well understood how proteostasis regulation is recruited by sensory input and how different aspects of proteostasis are temporally coordinated in response to neuronal activity.…”

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

“…These experiments will be critical for understanding when and where local or global signaling events impinge on EV biogenesis. Interestingly, activity-dependent delivery of Hrs to presynaptic terminals is critical for proteostasis of synaptic vesicle proteins (Birdsall et al, 2022; Sheehan et al, 2016). If MVEs are generated on-demand at synapses, Hrs transport could similarly underlie the activity-dependence of EV release, which has been reported in many (but not all) neuronal experimental systems, and remains poorly understood (Ataman et al, 2008; Faure et al, 2006; Lachenal et al, 2011; Lee et al, 2018; Vilcaes et al, 2021).…”