The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

Moretto, Edoardo; Miozzo, Federico; Longatti, Anna; Bonnet, Caroline; Coussen, Françoise; Jaudon, Fanny; Cingolani, Lorenzo A.; Passafaro, Maria

doi:10.7554/elife.76425

Cited by 3 publications

(3 citation statements)

References 63 publications

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“…The studies performed in HeLa cells unveiled a role of AP-4 in the Golgi and endosomes. A role of AP-4 in endosomes has been recently suggested in the regulation of AMPA receptor trafficking mediated by tetraspanin TSPAN5 in neurons (Moretto, Miozzo et al 2023). We found an increase presence of ApoER2 early, but not recycling endosomes in AP-4 deficient cells.…”

Section: Discussionmentioning

confidence: 99%

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

Caracci,

Pizarro,

Alarcón-Godoy

et al. 2023

Preprint

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Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes protein export from thetrans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4.AP4E1-knock-out (KO) HeLa cells and hippocampal neurons fromAp4e1-KO mice display increased Golgi localization of ApoER2. Furthermore, hippocampal neurons fromAp4e1-KO mice andAP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. Altogether, this work establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

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Section: Discussionmentioning

confidence: 99%

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

Caracci,

Pizarro,

Alarcón-Godoy

et al. 2023

Preprint

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“…AP-4 on the other hand has a less clear-cut role in polarized sorting. It has been proposed to form another somatodendritic vesicle population containing AMPA receptors (Matsuda et al, 2008;Moretto et al, 2023). However, AP-4 has also been implicated in the trafficking of autophagosomal, lysosomal and axonal proteins (Mattera et al, 2017;Pace et al, 2018;Ivankovic et al, 2020;Davies et al, 2022;Majumder et al, 2022).…”

Section: Traversing and Exiting The Golgi Apparatusmentioning

confidence: 99%

A voyage from the ER: spatiotemporal insights into polarized protein secretion in neurons

Kersten,

Farías

2023

Front. Cell Dev. Biol.

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To function properly, neurons must maintain a proteome that differs in their somatodendritic and axonal domain. This requires the polarized sorting of newly synthesized secretory and transmembrane proteins into different vesicle populations as they traverse the secretory pathway. Although the trans-Golgi-network is generally considered to be the main sorting hub, this sorting process may already begin at the ER and continue through the Golgi cisternae. At each step in the sorting process, specificity is conferred by adaptors, GTPases, tethers, and SNAREs. Besides this, local synthesis and unconventional protein secretion may contribute to the polarized proteome to enable rapid responses to stimuli. For some transmembrane proteins, some of the steps in the sorting process are well-studied. These will be highlighted here. The universal rules that govern polarized protein sorting remain unresolved, therefore we emphasize the need to approach this problem in an unbiased, top-down manner. Unraveling these rules will contribute to our understanding of neuronal development and function in health and disease.

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“…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 ).…”

Section: Introductionmentioning

confidence: 99%

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

Singh,

Das,

Sutradhar

et al. 2024

Preprint

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Rab4 GTPase organizes endosomal sorting essential for maintaining the balance between recycling and degradative pathways. Rab4 localizes to many cargos whose transport in neurons is critical for regulating neurotransmission and neuronal health. Furthermore, elevated Rab4 levels in the CNS are associated with synaptic atrophy and neurodegeneration in Drosophila and humans, respectively. However, how the transport of Rab4-associated vesicles is regulated in neurons remains unknown. Using in vivo time-lapse imaging of Drosophila larvae, we show that activation of insulin signaling via Dilp2 and dInR increases the anterograde velocity, run length, and flux of Rab4 vesicles in the axons. Molecularly, we show that activation of neuronal insulin signaling further activates Vps34, elevates the levels of PI(3)P on Rab4-associated vesicles, recruits Klp98a (a PI(3)P-binding kinesin-3 motor) and activates their anterograde transport. Together, these observations delineate the role of insulin signaling in regulating axonal transport and synaptic homeostasis.

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The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

Cited by 3 publications

References 63 publications

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

A voyage from the ER: spatiotemporal insights into polarized protein secretion in neurons

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

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