scholarly journals Sorting nexin 27 interactome in T-lymphocytes identifies zona occludens-2 dynamic redistribution at the immune synapse

Traffic ◽  
2017 ◽  
Vol 18 (8) ◽  
pp. 491-504 ◽  
Author(s):  
María Tello-Lafoz ◽  
Gonzalo Martínez-Martínez ◽  
Cristina Rodríguez-Rodríguez ◽  
Juan Pablo Albar ◽  
Morgan Huse ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Synapse ◽  
Sorting Nexin ◽  
Zona Occludens

scholarly journals Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

2020 ◽  
Vol 9 (1) ◽  
pp. 1759926 ◽  
Author(s):  
Ana Bello‐Gamboa ◽  
Marta Velasco ◽  
Solange Moreno ◽  
Gonzalo Herranz ◽  
Roxana Ilie ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Multivesicular Bodies ◽  
Actin Reorganization ◽  
Immune Synapse

scholarly journals Sorting nexin 27 rescues neuroligin 2 from lysosomal degradation to control inhibitory synapse number

2019 ◽  
Vol 476 (2) ◽  
pp. 293-306 ◽  
Author(s):  
Caroline S. Binda ◽  
Yasuko Nakamura ◽  
Jeremy M. Henley ◽  
Kevin A. Wilkinson
Keyword(s):  
Adaptor Protein ◽  
Inhibitory Synapse ◽  
Endosomal Trafficking ◽  
Dependent Manner ◽  
Lysosomal Degradation ◽  
Sorting Nexin ◽  
The Core ◽  
Cargo Proteins ◽  
Vacuolar Protein ◽  
Zona Occludens

Abstract Retromer is an evolutionarily conserved endosomal trafficking complex that mediates the retrieval of cargo proteins from a degradative pathway for sorting back to the cell surface. To promote cargo recycling, the core retromer trimer of VPS (vacuolar protein sorting)26, VPS29 and VPS35 recognises cargo either directly, or through an adaptor protein, the most well characterised of which is the PDZ [postsynaptic density 95 (PSD95), disk large, zona occludens] domain-containing sorting nexin SNX27. Neuroligins (NLGs) are postsynaptic trans-synaptic scaffold proteins that function in the clustering of postsynaptic proteins to maintain synaptic stability. Here, we show that each of the NLGs (NLG1–3) bind to SNX27 in a direct PDZ ligand-dependent manner. Depletion of SNX27 from neurons leads to a decrease in levels of each NLG protein and, for NLG2, this occurs as a result of enhanced lysosomal degradation. Notably, while depletion of the core retromer component VPS35 leads to a decrease in NLG1 and NLG3 levels, NLG2 is unaffected, suggesting that, for this cargo, SNX27 acts independently of retromer. Consistent with loss of SNX27 leading to enhanced lysosomal degradation of NLG2, knockdown of SNX27 results in fewer NLG2 clusters in cultured neurons, and loss of SNX27 or VPS35 reduces the size and number of gephyrin clusters. Together, these data indicate that NLGs are SNX27–retromer cargoes and suggest that SNX27–retromer controls inhibitory synapse number, at least in part through trafficking of NLG2.

scholarly journals The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin

2015 ◽  
Vol 26 (9) ◽  
pp. 1640-1651 ◽  
Author(s):  
Peter Hajdu ◽  
Geoffrey V. Martin ◽  
Ameet A. Chimote ◽  
Orsolya Szilagyi ◽  
Koichi Takimoto ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Actin Polymerization ◽  
Actin Dynamics ◽  
Actin Network ◽  
Immune Synapse ◽  
Proximity Ligation ◽  
C Terminus ◽  
Kv1.3 Channels ◽  
And Migration ◽  
Channel Polarization

Kv1.3 channels play a pivotal role in the activation and migration of T-lymphocytes. These functions are accompanied by the channels' polarization, which is essential for associated downstream events. However, the mechanisms that govern the membrane movement of Kv1.3 channels remain unclear. F-actin polymerization occurs concomitantly to channel polarization, implicating the actin cytoskeleton in this process. Here we show that cortactin, a factor initiating the actin network, controls the membrane mobilization of Kv1.3 channels. FRAP with EGFP-tagged Kv1.3 channels demonstrates that knocking down cortactin decreases the actin-based immobilization of the channels. Using various deletion and mutation constructs, we show that the SH3 motif of Kv1.3 mediates the channel immobilization. Proximity ligation assays indicate that deletion or mutation of the SH3 motif also disrupts interaction of the channel with cortactin. In T-lymphocytes, the interaction between HS1 (the cortactin homologue) and Kv1.3 occurs at the immune synapse and requires the channel's C-terminal domain. These results show that actin dynamics regulates the membrane motility of Kv1.3 channels. They also provide evidence that the SH3 motif of the channel and cortactin plays key roles in this process.

scholarly journals Polarity protein Par3 controls B-cell receptor dynamics and antigen extraction at the immune synapse

2015 ◽  
Vol 26 (7) ◽  
pp. 1273-1285 ◽  
Author(s):  
Anne Reversat ◽  
Maria-Isabel Yuseff ◽  
Danielle Lankar ◽  
Odile Malbec ◽  
Dorian Obino ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
B Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Microtubule Organizing Center ◽  
Antigen Uptake ◽  
Immune Synapse ◽  
Organizing Center ◽  
Dependent Transport

B-cell receptor (BCR) engagement with surface-tethered antigens leads to the formation of an immune synapse, which facilitates antigen uptake for presentation to T-lymphocytes. Antigen internalization and processing rely on the early dynein-dependent transport of BCR–antigen microclusters to the synapse center, as well as on the later polarization of the microtubule-organizing center (MTOC). MTOC repositioning allows the release of proteases and the delivery of MHC class II molecules at the synapse. Whether and how these events are coordinated have not been addressed. Here we show that the ancestral polarity protein Par3 promotes BCR–antigen microcluster gathering, as well as MTOC polarization and lysosome exocytosis, at the synapse by facilitating local dynein recruitment. Par3 is also required for antigen presentation to T-lymphocytes. Par3 therefore emerges as a key molecule in the coupling of the early and late events needed for efficient extraction and processing of immobilized antigen by B-cells.

scholarly journals Sorting Nexin 27 mediates PDZ‐directed trafficking of Zona‐Occludens (ZO)‐2 to the Tight Junction

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Christina Lynn Hueschen ◽  
Seth Paul Zimmerman ◽  
Sharon Lynn Milgram ◽  
Martin Peter Playford
Keyword(s):  
Tight Junction ◽  
Sorting Nexin ◽  
Zona Occludens

Diacylglycerol kinase control of protein kinase C

2019 ◽  
Vol 476 (8) ◽  
pp. 1205-1219 ◽  
Author(s):  
Isabel Mérida ◽  
Javier Arranz-Nicolás ◽  
Cristina Rodríguez-Rodríguez ◽  
Antonia Ávila-Flores
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
Spatial Organization ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Contact ◽  
Normal Brain ◽  
Sorting Nexin ◽  
Kinase C ◽  
Normal Brain Function

Abstract The diacylglycerol kinases (DGK) are lipid kinases that transform diacylglycerol (DAG) into phosphatidic acid (PA) in a reaction that terminates DAG-based signals. DGK provide negative regulation to conventional and novel protein kinase C (PKC) enzymes, limiting local DAG availability in a tissue- and subcellular-restricted manner. Defects in the expression/activity of certain DGK isoforms contribute substantially to cognitive impairment and mental disorders. Abnormal DGK overexpression in tumors facilitates invasion and resistance to chemotherapy preventing tumor immune destruction by tumor-infiltrating lymphocytes. Effective translation of these findings into therapeutic approaches demands a better knowledge of the physical and functional interactions between the DGK and PKC families. DGKζ is abundantly expressed in the nervous and immune system, where physically and functionally interacts with PKCα. The latest discoveries suggest that PDZ-mediated interaction facilitates spatial restriction of PKCα by DGKζ at the cell–cell contact sites in a mechanism where the two enzymes regulate each other. In T lymphocytes, DGKζ interaction with Sorting Nexin 27 (SNX27) guarantees the basal control of PKCα activation. SNX27 is a trafficking component required for normal brain function whose deficit has been linked to Alzheimer's disease (AD) pathogenesis. The enhanced PKCα activation as the result of SNX27 silencing in T lymphocytes aligns with the recent correlation found between gain-of-function PKCα mutations and AD and suggests that disruption of the mechanisms that provides a correct spatial organization of DGKζ and PKCα may lie at the basis of immune and neuronal synapse impairment.

scholarly journals Cutting Edge: Dynamic Redistribution of Tetraspanin CD81 at the Central Zone of the Immune Synapse in Both T Lymphocytes and APC

2002 ◽  
Vol 169 (12) ◽  
pp. 6691-6695 ◽  
Author(s):  
María Mittelbrunn ◽  
María Yáñez-Mó ◽  
David Sancho ◽  
Ángeles Ursa ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Lymphocytes ◽  
Central Zone ◽  
Cutting Edge ◽  
Immune Synapse

scholarly journals Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes

2017 ◽  
Vol 114 (32) ◽  
pp. E6585-E6594 ◽  
Author(s):  
Alex T. Ritter ◽  
Senta M. Kapnick ◽  
Sricharan Murugesan ◽  
Pamela L. Schwartzberg ◽  
Gillian M. Griffiths ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Immunological Synapse ◽  
Cortical Actin ◽  
Immune Synapse ◽  
Superresolution Microscopy ◽  
Lytic Granules ◽  
Infected Cells ◽  
Granule Secretion ◽  
Lytic Granule

CD8+ cytotoxic T lymphocytes (CTLs) eliminate virally infected cells through directed secretion of specialized lytic granules. Because a single CTL can kill multiple targets, degranulation must be tightly regulated. However, how CTLs regulate the termination of granule secretion remains unclear. Previous work demonstrated that centralized actin reduction at the immune synapse precedes degranulation. Using a combination of live confocal, total internal reflection fluorescence, and superresolution microscopy, we now show that, after granule fusion, actin recovers at the synapse and no further secretion is observed. Depolymerization of actin led to resumed granule secretion, suggesting that recovered actin acts as a barrier preventing sustained degranulation. Furthermore, RAB27a-deficient CTLs, which do not secrete cytotoxic granules, failed to recover actin at the synapse, suggesting that RAB27a-mediated granule secretion is required for actin recovery. Finally, we show that both actin clearance and recovery correlated with synaptic phosphatidylinositol 4,5-bisphosphate (PIP2) and that alterations in PIP2 at the immunological synapse regulate cortical actin in CTLs, providing a potential mechanism through which CTLs control cortical actin density. Our work provides insight into actin-related mechanisms regulating CTL secretion that may facilitate serial killing during immune responses.

scholarly journals Terminal transport of lytic granules to the immune synapse is mediated by the kinesin-1/Slp3/Rab27a complex

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3879-3889 ◽  
Author(s):  
Mathieu Kurowska ◽  
Nicolas Goudin ◽  
Nadine T. Nehme ◽  
Magali Court ◽  
Jérôme Garin ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Target Cells ◽  
Microtubule Organizing Center ◽  
Immune Synapse ◽  
Lytic Granules ◽  
Polarized Secretion ◽  
Organizing Center ◽  
Dependent Transport ◽  
Lytic Granule

Abstract Cytotoxic T lymphocytes kill target cells via the polarized secretion of cytotoxic granules at the immune synapse. The lytic granules are initially recruited around the polarized microtubule-organizing center. In a dynein-dependent transport process, the granules move along microtubules toward the microtubule-organizing center in the minus-end direction. Here, we found that a kinesin-1–dependent process is required for terminal transport and secretion of polarized lytic granule to the immune synapse. We show that synaptotagmin-like protein 3 (Slp3) is an effector of Rab27a in cytotoxic T lymphocytes and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain. Inhibition of the Rab27a/Slp3/kinesin-1 transport complex impairs lytic granule secretion. Our data provide further molecular insights into the key functional and regulatory mechanisms underlying the terminal transport of cytotoxic granules and the latter's secretion at the immune synapse.

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