Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

Giovanni, Jérôme Di; Sheng, Zu‐Hang

doi:10.15252/embj.201591125

Cited by 43 publications

(40 citation statements)

References 96 publications

(157 reference statements)

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“…In Snapin knockout mice, synaptic late endosomes are defective [28]. The authors showed that Snapin directly interacts with dynein intermediate chain and suggested that Snapin activates the retrograde transport of synaptic endosomes [29].…”

Section: Discussionmentioning

confidence: 99%

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

Niwa

et al. 2017

Current Biology

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Summary Axonal transport of synaptic vesicle precursors (SVPs) is essential for synapse development and function. The conserved ARF-like small GTPase ARL-8 is localized to SVPs and directly activates UNC-104/KIF1A, the axonal-transport kinesin for SVPs in C. elegans. It is not clear how ARL-8 is activated in this process. Here we show that part of the BLOC-1 related complex (BORC), previously shown to regulate lysosomal transport, is required to recruit and activate ARL-8 on SVPs. We found mutations in six BORC subunits-- blos-1/BLOS1, blos-2/BLOS2, snpn-1/Snapin, sam-4/Myrlysin, blos-7/Lyspersin and blos-9/MEF2BNB cause defects in axonal transport of SVPs, leading to ectopic accumulation of synaptic vesicles in the proximal axon. This phenotype is suppressed by constitutively active arl-8 or unc-104 mutants. Furthermore, SAM-4/Myrlysin, a subunit of BORC, promotes the GDP to GTP exchange of ARL-8 in vitro and recruits ARL-8 onto SVPs in vivo. Thus, BORC regulates the axonal transport of synaptic materials and synapse formation by controlling the nucleotide state of ARL-8. Interestingly, the other two subunits of BORC essential for lysosomal transport, kxd-1/KXD1 and blos-8/Diaskedin, are not required for the SVP transport, suggesting distinct subunit requirements for lysosomal and SVP trafficking.

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Section: Discussionmentioning

confidence: 99%

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

Niwa

et al. 2017

Current Biology

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“…12 In contrast, in neurons, the speed of retrograde delivery of endosomes from peripheral axons to the central soma is reduced, potentially impairing endosome-lysosome fusion. 12,13 RAB7 is necessary for endosome-lysosome fusion, 67 and in macrophages, RAB7 levels are not changed in SNAPIN-silenced macrophages, suggesting no increase of late endosome accumulation. Additionally, depletion of RAB7 in HeLa cells impairs cargo transfer from endosomes to the lysosomes, suggesting RAB7 is required for endosome-to-lysosome delivery.…”

Section: Ctse (Cathepsin E)mentioning

confidence: 97%

SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages

et al. 2016

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We previously observed that SNAPIN, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify SNAPIN's role in these cells, we employed siRNA to silence the expression of SNAPIN in primary human macrophages. Silencing SNAPIN resulted in swollen lysosomes with impaired CTSD (cathepsin D) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of SNAPIN. The acidification of lysosomes and accumulation of autolysosomes in SNAPINsilenced cells was inhibited, resulting in incomplete lysosomal hydrolysis and impaired macroautophagy/ autophagy flux. Mechanistic studies employing ratiometric color fluorescence on living cells demonstrated that the reduction of SNAPIN resulted in a modest reduction of H C pump activity; however, the more critical mechanism was a lysosomal proton leak. Overall, our results demonstrate that SNAPIN is critical in the maintenance of healthy lysosomes and autophagy through its role in lysosome acidification and autophagosome maturation in macrophages largely through preventing proton leak. These observations suggest an important role for SNAPIN and autophagy in the homeostasis of macrophages, particularly long-lived tissue resident macrophages.

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“…In neurons, BLOC‐1 is implicated in the biogenesis and release of synaptic vesicles in presynaptic terminals (Newell‐Litwa et al . ; Di Giovanni and Sheng ; Chen et al ., ). In addition, neurons from pallid mutant mice show impaired neurite outgrowth (Ghiani et al .…”

Section: Summary Of Cytohesin‐interacting Moleculesmentioning

confidence: 99%

Pallidin is a novel interacting protein for cytohesin‐2 and regulates the early endosomal pathway and dendritic formation in neurons

Ito

Fukaya

Saegusa

et al. 2018

Journal of Neurochemistry

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Cytohesin-2 is a member of the guanine nucleotide exchange factors for ADP ribosylation factor 1 (Arf1) and Arf6, which are small GTPases that regulate membrane traffic and actin dynamics. In this study, we first demonstrated that cytohesin-2 localized to the plasma membrane and vesicles in various subcellular compartment in hippocampal neurons by immunoelectron microscopy. Next, to understand the molecular network of cytohesin-2 in neurons, we conducted yeast two-hybrid screening of brain cDNA libraries using cytohesin-2 as bait and isolated pallidin, a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) involved in endosomal trafficking. Pallidin interacted specifically with cytohesin-2 among cytohesin family members. Glutathione S-transferase pull-down and immunoprecipitation assays further confirmed the formation of a protein complex between cytohesin-2 and pallidin. Immunofluorescence demonstrated that cytohesin-2 and pallidin partially colocalized in various subsets of endosomes immunopositive for EEA1, syntaxin 12, and LAMP2 in hippocampal neurons. Knockdown of pallidin or cytohesin-2 reduced cytoplasmic EEA1-positive early endosomes. Furthermore, knockdown of pallidin increased the total dendritic length of cultured hippocampal neurons, which was rescued by co-expression of wild-type pallidin but not a mutant lacking the ability to interact with cytohesin-2. In contrast, knockdown of cytohesin-2 had the opposite effect on total dendritic length. The present results suggested that the interaction between pallidin and cytohesin-2 may participate in various neuronal functions such as endosomal trafficking and dendritic formation in hippocampal neurons. Cover Image for this issue: doi: 10.1111/jnc.14197.

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Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

Cited by 43 publications

References 96 publications

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages

Pallidin is a novel interacting protein for cytohesin‐2 and regulates the early endosomal pathway and dendritic formation in neurons

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