Is there a place and role for endocytic <scp>TCR</scp> signaling?

Saveanu, Loredana; Zucchetti, Andrés E.; Evnouchidou, Irini; Ardouin, Laurence; Hivroz, Claire

doi:10.1111/imr.12764

Cited by 16 publications

(18 citation statements)

References 198 publications

(251 reference statements)

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“…Since VAMP7 has been shown to control membrane trafficking to and from the Golgi 54 , mislocalization of the mutant form of VAMP7 may have downstream consequences for T-cell function such as polarized transport of proteins or cell migration. The fact that, as shown here, localization of this key v-SNARE protein is regulated upon TCR triggering reinforces the link that exists between TCR-induced signaling and intracellular trafficking 55 .…”

Section: Resultssupporting

confidence: 82%

Dynamic palmitoylation events following T-cell receptor signaling

et al. 2020

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Palmitoylation is the reversible addition of palmitate to cysteine via a thioester linkage. The reversible nature of this modification makes it a prime candidate as a mechanism for regulating signal transduction in T-cell receptor signaling. Following stimulation of the T-cell receptor we find a number of proteins are newly palmitoylated, including those involved in vesicle-mediated transport and Ras signal transduction. Among these stimulation-dependent palmitoylation targets are the v-SNARE VAMP7, important for docking of vesicular LAT during TCR signaling, and the largely undescribed palmitoyl acyltransferase DHHC18 that is expressed in two isoforms in T cells. Using our newly developed On-Plate Palmitoylation Assay (OPPA), we show DHHC18 is capable of palmitoylating VAMP7 at Cys183. Cellular imaging shows that the palmitoylation-deficient protein fails to be retained at the Golgi and to localize to the immune synapse upon T cell activation.

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Section: Resultssupporting

confidence: 82%

Dynamic palmitoylation events following T-cell receptor signaling

et al. 2020

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“…It might also alter some cell functions such as polarized transport of proteins or cell migration. The fact that, as shown here, localization of this key v-SNARE protein is regulated upon TCR triggering reinforces the link that exists between TCR-induced signaling and intracellular trafficking 54 .…”

Section: Vamp7 Is Palmitoylated At Cys183 In Vitro and In Vivo And Issupporting

confidence: 82%

Dynamic Palmitoylation Events Following T-Cell Receptor Signaling

Morrison

Wegner

Zucchetti

et al. 2019

Preprint

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Palmitoylation is the reversible addition of palmitate to cysteine via a thioester linkage. Following stimulation of the T-cell receptor we find a number of proteins are newly palmitoylated, including those involved in vesiclemediated transport and Ras signal transduction. Among these stimulation-dependent palmitoylation targets are the v-SNARE VAMP7, important for docking of vesicular LAT during TCR signaling, and the largely undescribed palmitoyl acyltransferase DHHC18 that is expressed in two isoforms in T cells. Using our newly developed On-Plate Palmitoylation Assay (OPPA), we show DHHC18 is capable of palmitoylating VAMP7 at Cys183. Cellular imaging shows that the palmitoylation-deficient protein fails to be retained at the Golgi.The initial signaling events following the recognition of a peptide-MHC complex on an antigen-presenting cell (APC) by the T-cell receptor (TCR) involve a number of important molecules that must localize to the plasma membrane (PM) at the immunological synapse (IS). Palmitoylation, the reversible linking of 16-carbon palmitic acid to cysteines via a labile thioester bond, is one strategy used by several important TCR-signaling proteins to drive this localization to and from the membrane (e.g. the soluble Src-family kinases Lck and Fyn) or to and from liquid-ordered microdomains ("lipid rafts") within the membrane (e.g. the transmembrane scaffold LAT) 1 .Unlike other lipid modifications like myristoylation or prenylation, the reversible chemistry of the thioester bond allows palmitoylation to be both added to and removed from specific cysteines; indeed, enzymes have evolved to both add (e.g. the DHHC family of protein acyltransferases [PATs]) and remove (e.g. acyl protein thioesterase 1 [APT1] and ABHD17) palmitate from these sites in eukaryotes 2,3 . This has given rise to palmitoylation cycles, where proteins are palmitoylated in the ER/Golgi, cycled to the PM via vesicle trafficking and localized to the site of activity, then depalmitoylated and recycled back to the ER/Golgi 4 .Such cycles have become well-established in neuronal proteins like PSD-95, as well as the G-protein α subunits Gαi and Gαq and small GTPases H-Ras and N-Ras 4,5 , and pulse-chase experiments have shown that palmitoylation turnover can be accelerated following signaling stimuli, such as glutamate receptor activation with PSD-95, GTP binding of H-Ras, and GPCR signaling for Gα proteins 6-8 . In the context of T-cells, Lck has been shown to undergo relatively rapid palmitate turnover under resting conditions, which is accelerated following Fas receptor stimulation, and this palmitoylation is specifically catalyzed by DHHC21 at the PM 9 . A decrease in the palmitoylation of LAT has been observed in anergic T cells, which affects its ability to localize to lipid rafts and induce an effective stimulatory response 1,10 . Docking of vesicular LAT to the IS and downstream signaling also critically depend on palmitoylated SNARE proteins like SNAP-23 and VAMP7 11,12 . While these targeted approaches suggest the possi...

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“…This may be modulated by post-transcriptional modifications, such as phosphorylation and ubiquitination (Cenciarelli et al, 1992;D'Oro et al, 1997;Valitutti et al, 1997;Wang et al, 2001;Bonello et al, 2004;Balagopalan et al, 2007Balagopalan et al, , 2011Huang et al, 2010;Ivanova and Carpino, 2016). Worth noting, the existence of a transient endosomal/Golgi compartment where signaling may continue has been inferred from the presence of active kinases and phosphorylated signaling molecules associated with intracellular compartments after TCR engagement (Luton et al, 1997;Yudushkin and Vale, 2010;reviewed in Alcover et al, 2018;Saveanu et al, 2019;Evnouchidou et al, 2020).…”

Section: Vesicle Traffic Controls Tcr Signaling and The Cytoskeletonmentioning

confidence: 99%

Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions

Mastrogiovanni

Juzans

Alcover

et al. 2020

Front. Cell Dev. Biol.

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Dynamic localization of receptors and signaling molecules at the plasma membrane and within intracellular vesicular compartments is crucial for T lymphocyte sensing environmental cues, triggering membrane receptors, recruiting signaling molecules, and fine-tuning of intracellular signals. The orchestrated action of actin and microtubule cytoskeleton and intracellular vesicle traffic plays a key role in all these events that together ensure important steps in T cell physiology. These include extravasation and migration through lymphoid and peripheral tissues, T cell interactions with antigen-presenting cells, T cell receptor (TCR) triggering by cognate antigen-major histocompatibility complex (MHC) complexes, immunological synapse formation, cell activation, and effector functions. Cytoskeletal and vesicle traffic dynamics and their interplay are coordinated by a variety of regulatory molecules. Among them, polarity regulators and membrane-cytoskeleton linkers are master controllers of this interplay. Here, we review the various ways the T cell plasma membrane, receptors, and their signaling machinery interplay with the actin and microtubule cytoskeleton and with intracellular vesicular compartments. We highlight the importance of this fine-tuned crosstalk in three key stages of T cell biology involving cell polarization: T cell migration in response to chemokines, immunological synapse formation in response to antigen cues, and effector functions. Finally, we discuss two examples of perturbation of this interplay in pathological settings, such as HIV-1 infection and mutation of the polarity regulator and tumor suppressor adenomatous polyposis coli (Apc) that leads to familial polyposis and colorectal cancer.

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Is there a place and role for endocytic TCR signaling?

Cited by 16 publications

References 198 publications

Dynamic palmitoylation events following T-cell receptor signaling

Dynamic palmitoylation events following T-cell receptor signaling

Dynamic Palmitoylation Events Following T-Cell Receptor Signaling

Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions

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