Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons

Su, Qingning; Cai, Qian; Gerwin, Claudia; Smith, Carolyn L.; Sheng, Zu Hang

doi:10.1038/ncb1169

Cited by 138 publications

(159 citation statements)

References 48 publications

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“…Strong colocalization of Stx, Munc18, and FEZ1 in growth cones from young neurons and data from transgenic worms indicate that transport via FEZ1/ Kinesin-1 transport complexes play an important role in bringing Stx and Munc18 to the tips of rapidly developing axons during neuritogenesis. Thus, we identified a second transport complex for Stx distinct from, but that may act in conjunction with, the previously identified adaptor syntabulin that mediates Stx transport via another member of the Kinesin-1 family (KIF5B) (6,7). It will be interesting to clarify whether FEZ1 and syntabulin can functionally substitute for each other in the transport of Stxcontaining vesicles and whether their cargo spectrum is similar.…”

Section: Discussionmentioning

confidence: 99%

“…We first investigated how these proteins interact with Kinesin-1. Binding of Stx to Kinesin-1 is dependent on syntabulin, another motor adapter protein (6). Immunoprecipitation of Munc18 from cell lysates after cotransfection of Munc18 with Kinesin-1 (KIF5C) revealed both proteins do not directly interact (Fig.…”

Section: Fez1mentioning

confidence: 99%

“…Transport of syntaxin 1a (Stx), an essential component of the exocytotic release apparatus residing in the presynaptic plasma membrane, is clearly distinct from synaptic vesicle precursors and appears to involve a complex between Kinesin-1 and the Stx-binding protein syntabulin (6,7). Down-regulation or expression of dominant-negative syntabulin reduces but does not abolish membrane delivery of Stx, indicating the existence of other transport mechanisms (6). Moreover, proper intracellular trafficking of Stx and its function in exocytosis depends on Munc18 coexpression (8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

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Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylationdeficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases. T he formation and maintenance of presynaptic boutons are intricate but highly efficient processes during which the machinery for exocytosis and recycling of synaptic vesicles is assembled from preformed units. These units are delivered to the nascent synapse via molecular motor proteins of the kinesin superfamily (reviewed in Ref. 1).Although Kinesin-3 appears to be the main motor transporting synaptic vesicle precursors, recent evidence suggests that Kinesin-1 (KIF5) is also involved. In Drosophila, deletion of UNC-76/ fasciculation and elongation protein zeta 1 (FEZ1), a specific adaptor for Kinesin-1, left synaptic vesicles stranded in the axon (2, 3), showing that Kinesin-1 is needed at least during later phases of axonal transport. Transport of the synaptic vesicle protein synaptotagmin by the UNC-76/Kinesin-1 complex requires phosphorylation of UNC-76 by the UNC-51/ATG1 kinase, a prerequisite for UNC-76 to bind synaptotagmin (3). Deletion of this kinase phenocopies deletion of UNC-76. Indeed, phosphorylation-regulated interactions between cargo, adaptors, and kinesins have also been observed for other transport complexes such as the kinesin light chain/JIP1 (c-Jun N-terminal kinase-interacting protein 1) complex (4). This suggests that phosphorylation is a common mechanism for the regulation of kinesin-based transport complexes (5).Less is known about the involvement of Kinesin-1 in the transport of other classes of synaptic precursor vesicles. Transport of syntaxin 1a (Stx), an essential component of the exocytotic release apparatus residing in the presynaptic plasma membrane, is clearly distinct from synaptic vesicle precursors and appears to involve a complex between Kinesin-1 and the Stx-binding protein syntabulin (6, 7). Down-regulation or expression of dominant-negative syntabulin reduces but does not abolish membrane delivery of Stx, indicating the existence of other transport mechanisms (6). Moreover, proper intracellular trafficking of Stx and its function in exocytosis depends on Munc18 coexpression (8-14). Stx tra...

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Section: Discussionmentioning

confidence: 99%

Section: Fez1mentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Syntabulin is a linker molecule between syntaxin 1A (SYN1A) and the kinesin 1 family member 5B motor protein that delivers SYN1A‐containing vesicles to the presynaptic nerve terminal (Su, Cai, Gerwin, Smith, & Sheng, 2004). SYN1A interaction with the NH 2 ‐terminus of the dopamine transporter (DAT), to which cocaine binds, regulates the transporter by suppressing DAT channel activity (Carvelli, Blakely, & DeFelice, 2008).…”

Section: Discussionmentioning

confidence: 99%

Reading LINEs within the cocaine addicted brain

Doyle

Doucet-O’Hare²,

Hammond

et al. 2017

Brain and Behavior

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IntroductionLong interspersed element (LINE)‐1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine‐treated mice, and L1 retrotransposition was increased in cocaine‐treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain.MethodsPostmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488‐labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non‐neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non‐neuronal genomic DNA (gDNA) using L1‐seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom “L1‐seq” bioinformatics programs.ResultsPreviously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady‐state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA.ConclusionsWe conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.

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“…Recently, syntaxincontaining vesicles were shown to contain an adaptor protein that provided a link to the microtubule cytoskeleton. This particular adaptor, known as syntabulin, is bound to conventional kinesin I heavy chain (40). Such microtubuleassociated motor proteins interact and traverse along stabilized microtubules, both in vitro and in vivo, thus explaining why syntaxin 3 and PSMA were not directed in a nonpolarized fashion in Taxotere-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Differing effects of microtubule depolymerizing and stabilizing chemotherapeutic agents on t-SNARE–mediated apical targeting of prostate-specific membrane antigen

Christiansen¹,

Weimbs²,

Bander³

et al. 2006

Molecular Cancer Therapeutics

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Prostate-specific membrane antigen (PSMA) is a protein up-regulated in the vast majority of prostate cancers. Antibodies to PSMA have proved highly specific for prostate cancer cells, and the therapeutic potential of such antibodies is currently being assessed in clinical trials. We have previously shown that PSMA at the cell surface of polarized epithelial cells is predominantly expressed at the apical plasma membrane and that microtubule depolymerization abolishes apical PSMA targeting. In the current report, we implicate a functional role for a target membrane soluble N -ethylmaleimide-sensitive factor adaptor protein receptor, syntaxin 3, in the microtubuledependent apical targeting of PSMA. PSMA and syntaxin 3 are similarly localized to the apical plasma membrane of the prostatic epithelium and Madin-Darby canine kidney cells.

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Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons

Cited by 138 publications

References 48 publications

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Reading LINEs within the cocaine addicted brain

Differing effects of microtubule depolymerizing and stabilizing chemotherapeutic agents on t-SNARE–mediated apical targeting of prostate-specific membrane antigen

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