IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses

Evnouchidou, Irini; Chappert, Pascal; Benadda, Samira; Zucchetti, Andrés E.; Weimershaus, Mirjana; Bens, Marcelle; Caillens, Vivien; Koumantou, Despoina; Lotersztajn, Sophie; Endert, Peter Van; Davoust, Jean; Guermonprez, Pierre; Hivroz, Claire; Gross, David-Alexandre; Saveanu, Loredana

doi:10.1038/s41467-020-16471-7

Cited by 28 publications

(47 citation statements)

References 61 publications

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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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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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“…Initially, we compared the specificity of GOH-1 with 2 commercially available anti-P-LAP/IRAP monoclonal antibodies (D7C5 and 3E1) by western blot analysis (Pan et al, 2019;Evnouchidou et al, 2020). As shown in Figure 1, GOH-1, and D7C5 recognized the same protein with a molecular weight of 140-165 kDa, which was expected to be P-LAP/IRAP.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we performed immunohistochemical analyses using D7C5 to rule out the possibility of non-specific interaction between GOH-1 and sample proteins prepared from several sub-regions of the brain. Frequent usage of D7C5 for immunohistochemical analysis has been previously established (Sun et al, 2014;Evnouchidou et al, 2020). Figure 2B shows the immunohistochemical localization of P-LAP/IRAP and AVP in various regions of the murine brain.…”

Section: Resultsmentioning

confidence: 99%

Reciprocal Expression Patterns of Placental Leucine Aminopeptidase/Insulin-Regulated Aminopeptidase and Vasopressin in the Murine Brain

Goto

Nakamura

Ogawa

et al. 2020

Front. Mol. Biosci.

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Placental leucine aminopeptidase/insulin-regulated aminopeptidase (P-LAP/IRAP) regulates vasopressin and oxytocin levels in the brain and peripheral tissues by controlled degradation of these peptides. In this study, we determined the relationship between P-LAP/IRAP and vasopressin levels in subregions of the murine brain. P-LAP/IRAP expression was observed in almost all brain regions. The expression patterns of P-LAP/IRAP and vasopressin indicated that cells expressing one of these protein/peptide were distinct from those expressing the other, although there was significant overlap between the expression regions. In addition, we found reciprocal diurnal rhythm patterns in P-LAP/IRAP and arginine vasopressin (AVP) expression in the hippocampus and pituitary gland. Further, synchronously cultured PC12 cells on treatment with nerve growth factor (NGF) showed circadian expression patterns of P-LAP/IRAP and enzymatic activity during 24 h of incubation. Considering that vasopressin is one of the most efficient peptide substrates of P-LAP/IRAP, these results suggest a possible feedback loop between P-LAP/IRAP and vasopressin expression, that regulates the function of these substrate peptides of the enzyme via translocation of P-LAP/IRAP from intracellular vesicles to the plasma membrane in brain cells. These findings provide novel insights into the functions of P-LAP/IRAP in the brain and suggest the involvement of these peptides in modulation of brain AVP functions in hyperosmolality, memory, learning, and circadian rhythm.

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“…These results as well as previous studies showing that CD3ζ and LAT are present in different exocytic compartments [11] demonstrate that different signaling molecules involved in TCR triggering are not "traveling" together. They also suggest that they can form different signalosomes in different intracellular localizations [46].…”

Section: Discussionmentioning

confidence: 99%

Retrograde and Anterograde Transport of Lat-Vesicles during the Immunological Synapse Formation: Defining the Finely-Tuned Mechanism

Sáez

Dogniaux

Shafaq-Zadah

et al. 2021

Cells

Self Cite

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LAT is an important player of the signaling cascade induced by TCR activation. This adapter molecule is present at the plasma membrane of T lymphocytes and more abundantly in intracellular compartments. Upon T cell activation the intracellular pool of LAT is recruited to the immune synapse (IS). We previously described two pathways controlling LAT trafficking: retrograde transport from endosomes to the TGN, and anterograde traffic from the Golgi to the IS. We address the specific role of four proteins, the GTPase Rab6, the t-SNARE syntaxin-16, the v-SNARE VAMP7 and the golgin GMAP210, in each pathway. Using different methods (endocytosis and Golgi trap assays, confocal and TIRF microscopy, TCR-signalosome pull down) we show that syntaxin-16 is regulating the retrograde transport of LAT whereas VAMP7 is regulating the anterograde transport. Moreover, GMAP210 and Rab6, known to contribute to both pathways, are in our cellular context, specifically and respectively, involved in anterograde and retrograde transport of LAT. Altogether, our data describe how retrograde and anterograde pathways coordinate LAT enrichment at the IS and point to the Golgi as a central hub for the polarized recruitment of LAT to the IS. The role that this finely-tuned transport of signaling molecules plays in T-cell activation is discussed.

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IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses

Cited by 28 publications

References 61 publications

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

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

Reciprocal Expression Patterns of Placental Leucine Aminopeptidase/Insulin-Regulated Aminopeptidase and Vasopressin in the Murine Brain

Retrograde and Anterograde Transport of Lat-Vesicles during the Immunological Synapse Formation: Defining the Finely-Tuned Mechanism

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