Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3

Abstract

Neuregulins (NRGs) are EGF-like ligands associated with cognitive disorders. Unprocessed proNRG3 is cleaved by BACE1 to generate the mature membrane-bound NRG3 ligand, but the subcellular site of proNRG3 cleavage, mechanisms underlying its transport into axons, and presynaptic accumulation remain unknown. Using an optogenetic proNRG3 cleavage reporter (LA143-NRG3), we investigate the spatial-temporal dynamics of NRG3 processing and sorting in neurons. In dark conditions, unprocessed LA143-NRG3 is retained in the trans-Golgi network but, upon photoactivation, is cleaved by BACE1 and released from the TGN. Mature NRG3 then emerges on the somatodendritic plasma membrane from where it is re-endocytosed and anterogradely transported on Rab4+ vesicles into axons via transcytosis. By contrast, the BACE1 substrate APP is sorted into axons on Rab11+ vesicles. Lastly, by a mechanism we denote “trans-synaptic retention,” NRG3 accumulates at presynaptic terminals by stable interaction with its receptor ErbB4 on postsynaptic GABAergic interneurons. We propose that trans-synaptic retention may account for polarized expression of other neuronal transmembrane ligands and receptors.

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

“…Location, and hence the activity, of NRG3 depends in its processing ( Vullhorst et al, 2017 ). In the mouse, the unprocessed isoform accumulates in the cell body, while the processed protein, including proteolytically cleaved portions of it, are transported to other subcellular locations, the N-terminal fragment of NRG3 can for instance be transported to the cell membrane of the neurites, where it can interact with the postsynaptic ErbB4 receptors ( Ahmad et al, 2022 ). Interestingly, the N-terminus of NRG3 is also the site of the selective sweep in modern humans as compared to Neanderthals ( Green et al, 2010 ).…”

Insulin signaling accelerates the anterograde movement of Rab4 vesicles in axons through Klp98A/KIF16B recruitment via Vps34-PI3Kinase

“…Rab4 activation induces its recruitment onto vesicles which subsequently activates the vesicle trafficking through kinesin and dynein motors. Rab4 localizes to and transports vesicles carrying various cargos like tetraspanins ( Moretto et al, 2023 ), neuregulins ( Ahmad et al, 2022 ), integrins ( Shin et al, 2021 ), and astrotactins ( Behesti et al, 2018 ) regulating integral neuronal processes like trafficking and degradation of surface proteins, synapse formation, maturation, and maintenance. Unsurprisingly, a few of these cargo are also implicated in neurodevelopmental ( Behesti et al, 2018 ) and psychiatric disorders ( Ahmad et al, 2022 ).…”

“…Rab4 localizes to and transports vesicles carrying various cargos like tetraspanins ( Moretto et al, 2023 ), neuregulins ( Ahmad et al, 2022 ), integrins ( Shin et al, 2021 ), and astrotactins ( Behesti et al, 2018 ) regulating integral neuronal processes like trafficking and degradation of surface proteins, synapse formation, maturation, and maintenance. Unsurprisingly, a few of these cargo are also implicated in neurodevelopmental ( Behesti et al, 2018 ) and psychiatric disorders ( Ahmad et al, 2022 ). On the other hand, overactivation of Rab4 at the presynaptic terminals induces synaptic atrophy in Drosophila .…”

Disruption of the FMN-A524 interaction cascade and Glu513-induced collapse of the hydrophobic barrier promotes light-induced Jα-helix unfolding in AsLOV2

“…LOV domains are found in plants 7,8 , bacteria 7,9 , fungi [10][11][12][13] and algae 14,15 . These domains are instrumental in the development of artificial photoswitches that enable spatio-temporally precise regulation of the active and inactive states of the target proteins [16][17][18][19][20][21][22][23][24][25] . Light-Oxygen-Voltage domain of Avena sativa (AsLOV2) is being widely used in the development of these photoswitches such as the LINuS (regulates gene expression and entry to mitosis) 20 , LEXY (control over the export proteins in cell) 23 , LOV-TAP (regulates the TrpR binding to the DNA) 25 and BLISS (controls protein conjugation) 17 .…”

“…This structural transition is a reversible process with timescales of unfolding and folding in microseconds and seconds, respectively 29 . This characteristic feature forms a basis for LOV2 to be used in photoswitching applications [16][17][18][19][20][21][22][23][24][25] .…”