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Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs.

ABSTRACT: Activity-dependent changes in synaptic strength have long been postulated as cellular correlates of learning and memory. Long-term potentiation (LTP), a well characterized form of synaptic plasticity, is often expressed as an increase in the number of postsynaptic AMPA-type glutamate receptors (AMPARs). Although the precise molecular mechanisms governing LTP remain elusive, this study identifies one member of the sorting nexin family, Sorting Nexin 27 (SNX27), as a critical component in this process. The ability of sorting nexins to bind specific phospholipids as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting. Here, we demonstrate that SNX27 binds to AMPARs, and that this interaction is regulated in an activity-dependent manner. Furthermore, we provide evidence that SNX27 is synaptically enriched and its level of expression regulates targeting of AMPARs to the neuronal surface. Loss of SNX27 abolishes recruitment of surface AMPARs during chemical LTP. Collectively, our data suggest a role for SNX27 in modulating synaptic plasticity through regulated interaction with AMPARs.

SUBMITTER: Hussain NK

PROVIDER: S-EPMC4136608 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs.

Hussain Natasha K NK Diering Graham H GH Sole Jonathan J Anggono Victor V Huganir Richard L RL

Proceedings of the National Academy of Sciences of the United States of America 20140728 32

Activity-dependent changes in synaptic strength have long been postulated as cellular correlates of learning and memory. Long-term potentiation (LTP), a well characterized form of synaptic plasticity, is often expressed as an increase in the number of postsynaptic AMPA-type glutamate receptors (AMPARs). Although the precise molecular mechanisms governing LTP remain elusive, this study identifies one member of the sorting nexin family, Sorting Nexin 27 (SNX27), as a critical component in this pro ...[more]

PMID: 25071192

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Project description:Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially cardiac hypertrophy and heart failure, are lacking. Here, we ask whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. An increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) mice and Snx3 transgenic (Snx3-cTg) mice were generated to evaluate the role of Snx3 in myocardial hypertrophy, fibrosis, and heart function by morphology, echocardiography, histological staining, and hypertrophic biomarkers. We report that Snx3-cKO in mice significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy at 12 weeks. Conversely, Snx3-cTg mice were more susceptible to ISO-induced cardiac hypertrophy at 12 weeks and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry, immunofluorescent staining, co-immunoprecipitation, localized surface plasmon resonance, and proximity ligation assay were performed to examine the direct interaction of SNX3-retromer with signal transducer and activator of transcription 3 (STAT3). We discovered that STAT3 was a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at EE. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. The pharmacological inhibition or knockdown of STAT3 reversed SNX3 overexpression-induced myocardial injury. STAT3 overexpression blunts the beneficial function of SNX3 knockdown on hypertrophic cardiomyocytes. We show that SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.

Project description:Sorting nexin 27 (SNX27) association to the retromer complex mediates intracellular trafficking of cargoes containing PSD95/Dlg1/ZO-1 (PDZ)-binding C-terminal sequences from endosomes to the cell surface, preventing their lysosomal degradation. Antigen recognition by T lymphocyte leads to the formation of a highly organized structure named the immune synapse (IS), which ensures cell-cell communication and sustained T cell activation. At the neuronal synapse, SNX27 recycles PDZ-binding receptors and its defective expression is associated with synaptic dysfunction and cognitive impairment. In T lymphocytes, SNX27 was found localized at recycling endosomal compartments that polarized to the IS, suggesting a function in polarized traffic to this structure. Proteomic analysis of PDZ-SNX27 interactors during IS formation identify proteins with known functions in cytoskeletal reorganization and lipid regulation, such as diacylglycerol (DAG) kinase (DGK) ζ, as well as components of the retromer and WASH complex. In this study, we investigated the consequences of SNX27 deficiency in cytoskeletal reorganization during IS formation. Our analyses demonstrate that SNX27 controls the polarization towards the cell-cell interface of the PDZ-interacting cargoes DGKζ and the retromer subunit vacuolar protein sorting protein 26, among others. SNX27 silencing abolishes the formation of a DAG gradient at the IS and prevents re-localization of the dynactin complex component dynactin-1/p150Glued, two events that correlate with impaired microtubule organizing center translocation (MTOC). SNX27 silenced cells show marked alteration in cytoskeleton organization including a failure in the organization of the microtubule network and defects in actin clearance at the IS. Reduced SNX27 expression was also found to hinder the arrangement of signaling microclusters at the IS, as well as the polarization of the secretory machinery towards the antigen presenting cells. Our results broaden the knowledge of SNX27 function in T lymphocytes by showing a function in modulating IS organization through regulated trafficking of cargoes.

Dataset Information

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs.

Publications

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs.

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