VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites

Larghi, Paola; Williamson, David J.; Carpier, Jean-Marie; Dogniaux, Stéphanie; Chemin, Karine; Bohineust, Armelle; Danglot, Lydia; Gaus, Katharina; Galli, Thierry; Hivroz, Claire

doi:10.1038/ni.2609

Cited by 109 publications

(203 citation statements)

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“…In conclusion, VAMP7 KO MEFs show phenotypes clearly related to the traffic of lipids and proteins known to reside in membrane domains. While these phenotypic traits do not preclude cell and organism life, 55,56 they may nevertheless induce profound signaling defects 20 which largely remain to explore. Further studies are required to address the impact of this mechanism in the organism and also how a v-SNARE which primarily mediates membrane fusion may also be required at earlier stages of membrane traffic like sorting of some components of membrane domains.…”

Section: Discussionmentioning

confidence: 99%

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Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

et al. 2015

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Keywords: exocytosis, Golgi apparatus, SNARE, sphingolipids, TI-VAMP/VAMP7 Abbreviations: BFA, Brefeldin A; Cer, Ceramide; ER, Endoplasmic Reticulum; GlcCer, Glucosylceramide; GM3, ganglioside monosialic acid 3; GPI, Glycosylphosphatidylinositol; GSL, Glycosphingolipids; LC, Long Chain; PI, Phosphatidylinositide; PM, Plasma Membrane; SM, Sphingomyelin; TGN, D Trans-Golgi Network; TI-VAMP/VAMP7, Tetanus neurotoxin-insensitive vesicle-associated membrane protein / Vesicle associated membrane protein 7; VLC, very long vhain; VSVG, Vesicular Stomatitis Virus GlycoproteinBiological membranes in eukaryotes contain a large variety of proteins and lipids often distributed in domains in plasma membrane and endomembranes. Molecular mechanisms responsible for the transport and the organization of these membrane domains along the secretory pathway still remain elusive. Here we show that vesicular SNARE TI-VAMP/VAMP7 plays a major role in membrane domains composition and transport. We found that the transport of exogenous and endogenous GPI-anchored proteins was altered in fibroblasts isolated from VAMP7-knockout mice. Furthermore, disassembly and reformation of the Golgi apparatus induced by Brefeldin A treatment and washout were impaired in VAMP7-depleted cells, suggesting that loss of VAMP7 expression alters biochemical properties and dynamics of the Golgi apparatus. In addition, lipid profiles from these knockout cells indicated a defect in glycosphingolipids homeostasis. We conclude that VAMP7 is required for effective transport of GPI-anchored proteins to cell surface and that VAMP7-dependent transport contributes to both sphingolipids and Golgi homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…18 In addition, VAMP7 is involved in the transport of GLUT1 and Lat, two other membrane domain associated proteins. 19,20 Altogether, these findings led us to hypothesize a more direct contribution of VAMP7 in membrane organization and membrane domains homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

et al. 2015

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“…2011) put forward a role for LAT vesicles in TCR signaling, challenging previous studies that demonstrated the requirement of LAT plasma membrane oligomerization and cis phosphorylation (Houtman et al, 2006) for TCR signal transduction. Moreover, Larghi et al (2013) very recently proposed that a VAMP7-mediated LAT vesicle docking to the synapse was responsible for TCR signaling. In contrast, another recent work (Balagopalan et al, 2013), using a CD4-LAT chimeric protein, proposed that it is mainly plasma membrane LAT that is phosphorylated and incorporated into microclusters, with minor influence from its vesicular pool.…”

Section: Methodsmentioning

confidence: 99%

Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse

Soares¹,

Henriques²,

Sachse³

et al. 2013

J Gen Physiol

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Abbreviations used: dSTORM, direct stochastic optical reconstruction microscopy; MAL, myelin and lymphocyte; Syt7, synaptotagmin-7; TIRF, total internal reflection fluorescence.M.-I. Thoulouze and A. Alcover contributed equally to this paper. Fig. 1, D and H). LAT vesicular compartment co-localized with Rab27a (35%) and Rab37 (30%; Fig. 1, M and N), two Rab molecules known to regulate cytokine and cytotoxic granule exocytosis in CD4 + and CD8 + T cells, respectively (Stinchcombe et al., 2001;Huse et al., 2006). TCR peripheral vesicles colocalized to the fast recycling Rab4b compartment (8%), whereas its core co-localized to Rab3d-(25%) and Rab8b-regulated (30%) exocytic compartments (Huse et al., 2006;Fukuda, 2008; Fig. 1, Q-S). Noteworthy, the secretory v-SNARE protein Ti-VAMP (Chaineau et al., 2009) co-localized with both LAT (30%) and TCR (30%) vesicular compartments (Fig. 1, O and W). Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse LAT and TCR vesicular release is regulated by calcium and synaptotagmin-7The traffic regulators present in LAT and TCR vesicles (Fig. 1) have been reported to be involved in stimulus-induced exocytosis at cytotoxic synapses (Ménager et al., 2007; MarcetPalacios et al., 2008). To pinpoint the molecular mechanism regulating Lck, LAT, and TCR release from vesicular compartments, we assessed the role of calcium, a known regulator of stimulus-dependent exocytosis (Stojilkovic, 2005;Pang and Südhof, 2010). To increase cytosolic calcium levels, we treated CD4 T cells either with thapsigargin or ionomycin. To accurately quantify Lck, LAT, and TCR distribution between intracellular vesicles and the plasma membrane, we stained for surface CD2 and then used it to automatically segment the plasma membrane. The resulting automated mask delimiting the internal and external outlines of the plasma membrane allowed us to discriminate and quantify the subcellular distribution (plasma membrane versus vesicular compartment) of our proteins of interest (materials and methods; unpublished data). We found LAT and TCR distribution to the vesicular compartment to be higher than anticipated by others (Bonello et al., 2004), 75% (Fig. 2, A, B, H, and I). In fact, through plasma membrane segmentation, we were able to distinguish plasma membrane-resident LAT and TCR from their intracellular compartments and subcortical vesicles, within the limits of the confocal microscopy resolution (unpublished data). Lck displayed a higher plasma membrane distribution with 25% in intracellular vesicles (Fig. 2, C and J; and not depicted).Consistent with LAT localization in Rab27a and Rab37 exocytic compartments, increased cytosolic calcium led to a clear release of its vesicular compartment into the plasma membrane (Fig. 2, A, I, and O; and not depicted). In agreement with TCR-segregated distribution into a Rab3d and Rab8b exocytic compartment and also into Rab4b rapid recycling endosomes, cytosolic calcium increase induced an inc...

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“…A v-SNARE (soluble N-ethylmaleimide-sensitive protein-attached protein receptor) protein VAMP7 guides these vesicles into the plasma membrane potentially by docking to the t-SNARE proteins, surprisingly, in a mechanism that does not involve actual membrane fusion. 14 These results suggest that components of the molecular machinery utilized in trafficking of synaptic vesicles in the neuronal synapse such as SNAREs and small Rab GTPases play an important role in the trafficking of subsynaptic vesicles in T cells to activate intracellular signaling pathways. However, the importance of vesicles in TCR signaling has been uncovered only recently and the identity and functions of these subsynaptic vesicles in T cell activation needs further investigation.…”

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confidence: 90%

A large Rab GTPase family in a small GTPase world

2016

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More than 60 Rab GTPases exist in the human genome to regulate vesicle trafficking between organelles. Rab GTPases are members of the Ras GTPase superfamily that broadly control budding, uncoating, motility and fusion of vesicles in most cell types. Rab proteins interconvert between active, GTP-bound form and inactive, GDP-bound form. In their active conformation, they interact with various effector molecules to carry out diverse functions. Rab GTPases are usually small containing only a GTPase domain with a C-terminal prenylation site for membrane anchoring. Recently, we identified a large G protein, CRACR2A (CRAC channel regulator 2A), which uncovers novel functions of Rab GTPases. First, CRACR2A encodes a large Rab GTPase containing multiple functional domains contrary to small Rab GTPases. Second, CRACR2A plays an unexpected role in regulating intracellular signaling pathways important for T cell activation, unlike the canonical role of small Rab GTPases. Vesicles containing CRACR2A bud out from the proximal Golgi area and translocate into the immunological synapse to activate these signaling pathways. Third, instead of recycling, CRACR2A is consumed by a unidirectional pathway. These events are sequentially regulated by prenylation, GTP binding, protein interaction with a signaling adaptor Vav1, and degradation. Together, our findings reveal a novel function of a large Rab GTPase in intracellular signaling pathways, which may be shared by other large Rab GTPases, Rab44 and Rab45.

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VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites

Cited by 109 publications

References 50 publications

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse

A large Rab GTPase family in a small GTPase world

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