INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells

Andrés-Delgado, Laura; Antón, Olga M.; Bartolini, Francesca; Ruiz-Sáenz, Ana; Correas, Isabel; Gundersen, Gregg G.; Alonso, Miguel A.

doi:10.1083/jcb.201202137

Cited by 77 publications

(78 citation statements)

References 65 publications

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“…The effect of Taxol on traction enhancement is more modest compared with nocodazole because Taxol has a milder effect on reducing dynamic MTs than nocodazole (as observed qualitatively from time-lapse images). Our results, however, do not entirely preclude the involvement of stable MTs, for example, with acetylated (19) and detyrosinated (21) tubulin, in regulating cellular contractility.…”

Section: Discussionmentioning

confidence: 59%

“…For example, overexpression of histone deacetylase 6, which deacetylates tubulin, results in defective MTOC translocation (19). A similar phenotype is observed when formins (including DIA1, FMNL1, and INF2), which are capable of inducing MT acetylation (20), are depleted (5,21). On the other hand, the biological functions of the MT cytoskeleton after the MTOC has translocated are less understood.…”

mentioning

confidence: 82%

“…Most previous studies on the role of MTs in T-cell activation have focused on the rapid translocation of the MTOC upon pMHC ligation (25,26,57) and the molecular mechanisms that underlie this process (5,19,21,58), The consensus view from these studies has been that the MT cytoskeleton acts as a scaffold, holding lytic granules and guiding centrosomal reorientation toward the APC for directional secretion. Although stable MTs have been demonstrated to be essential for MTOC translocation, our work identifies a role for dynamic MTs in regulating force generation at the cell periphery.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic microtubules regulate cellular contractility during T-cell activation

Hui

Upadhyaya

2017

Proc. Natl. Acad. Sci. U.S.A.

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T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell-substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.T lymphocytes, central players in the adaptive immune response, are activated when T-cell receptors (TCRs) on their surface recognize cognate peptide-major histocompatibility complex (pMHC) expressed on the surface of antigen-presenting cells (APCs). A burst of actin polymerization is triggered upon TCR stimulation (1), leading to an enhancement of the cell/APC contact area as the T cell spreads over the surface of the APC (2) and the formation of a macromolecular protein assembly known as the immunological synapse (IS) (3, 4). Accompanying IS formation, T cells also undergo a rapid polarization of the microtubule (MT) cytoskeleton, within 1-2 min after initial contact, that facilitates directional secretion of cytokines and cytolytic factors toward the APC (5-7). Therefore, the contact zone between T cells and APCs is a site at which the MT and actin cytoskeletons could potentially interact to regulate signaling.Recent studies have established that T cells generate significant traction stresses at the cell-cell interface, albeit relatively weak compared with adherent cells (8-11). These forces, which peak 5-10 min after stimulation, facilitate T-cell activation, in part, by inducing conformational changes in the TCR-CD3 complex (12-15). Although actin polymerization/depolymerization dynamics are essential for T cells to maintain dynamic traction stresses and to drive calcium influx and integrin affinity maturation (9, 16, 17), the regulatory pathways that control these cytoskeletal forces are not completely understood. In particular, whether and how the polarized MT cytoskeleton interacts with the actin cytoskeleton and regulates force generation at the T-cell-APC contact remain open questions.MTs in the cell exist in two populations: dynamic/tyrosinated MTs and stable MTs that have undergone posttranslational modifications, including detyrosination and acetylation (18). Previous studies of T-cell activation have elucidated that microtubuleorganizing center (MTOC) translocation is associated with the formati...

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Dynamic microtubules regulate cellular contractility during T-cell activation

Hui

Upadhyaya

2017

Proc. Natl. Acad. Sci. U.S.A.

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Section: Vesicular Traffic At the Ismentioning

confidence: 99%

“…Whether CD3ζ vesicles from the IS correspond to Lck vesicles at the pericentrosomal region and can cycle between the intracellular compartment of signaling molecules and the IS will require further investigation. Future studies should also address whether this traffic relates to MAL-mediated transport of Lck and possibly controlled by the detyrosination of microtubules promoted by IFN2 [46].In addition, there is intense traffic associated with the shutdown of the T cell signal. Several studies suggest that an intracellular signalling component, which is dependent on vesicular trafficking beneath the IS, regulates cell surface derived TCR signalling.…”

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confidence: 99%

Immune synapse: conductor of orchestrated organelle movement

Martín-Cófreces¹,

Baixauli²,

Sánchez-Madrid³

2014

Trends in Cell Biology

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SummaryTo ensure proper cell function, intracellular organelles are not randomly distributed within the cell, but polarized and highly constrained by the cytoskeleton and associated adaptor proteins. This relationship between distribution and function was originally found in neurons and epithelial cells; however, recent evidence suggests that it is a more general phenomenon that occurs in many highly specialized cells including the immune T cells. Recent studies reveal that the orchestrated redistribution of organelles is dependent on antigen specific activation and immune-synapse formation of T cells. This review highlights the functional implications of organelle polarization in early T cell activation and examines recent findings on how the immune synapse sets the rhythm of organelle motion and the spread of the activation signal to the nucleus. KeywordsImmune synapse; microcluster; signalosome; mitochondria; vesicle; microtubule Overview of the immune synapseT cell activation starts with an initial wave of signalling that depends on the activation of surface receptors, but subsequent propagation of the signal appears to depend on intracellular compartments, in a sequence driven by the actin and tubulin cytoskeletons [1]. The study of neural synapses highlighted the importance of cell polarity and the specific localization of organelles and clusters of receptors at the pre-and post-synaptic terminals. Despite its transient nature, recent evidence shows that the immune synapse (IS) shares these same neuronal features.The IS is the interface between a T lymphocyte and an antigen presenting cell (APC). During the formation and stabilization of the IS, membrane microdomains and the cytoskeleton reorganize and promote the segregation of membrane and intracellular signaling proteins within the T cell, such as the T cell receptor (TCR), integrins, tyrosine Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts kinases and scaffold proteins such as Linker for activation of T cells (LAT) (Figure 1 and Glossary). The TCR and associated molecules (TCR signalosomes) form microclusters that move to congregate in the central area (central supramolecular activation cluster; cSMAC) of the IS, whereas adhesion receptors such as integrins reorganize in a surrounding external ring called the peripheral or pSMAC ( Figure 2) [2]. In addition, phosphorylation and dephosphorylation, protein-protein interactions and degradation of important molecules such as the TCR-accompanying CD3 complex, tyrosine kinases, phosphatases and adaptor molecules also control receptor activation [3,4]. The polarization of several organelles occurs during T cell stimulation with important roles, such as the centrosome, Golgi apparatus, mitochondria, endoplasmic reticulum and the multivesicular bodies (MVB) [5][6][7][8][9][10]. These rearrangements at the IS promote the activation of signaling pathways that propagate to the nucleus. Signals activating nuclear transcription factors in combination with polarity proteins, such as partit...

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Inverted formins: A subfamily of atypical formins

2017

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Formins are a family of regulators of actin and microtubule dynamics that are present in almost all eukaryotes. These proteins are involved in many cellular processes, including cytokinesis, stress fiber formation, and cell polarization. Here we review one sub-family of formins, the inverted formins. Inverted formins as a group break several formin stereotypes, having atypical biochemical properties and domain organization, and they have been linked to kidney disease and neuropathy in humans. In this review, we will explore recent research on members of the inverted formin sub-family in mammals, zebrafish, fruit flies, and worms.

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INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells

Abstract: The formin INF2 promotes the formation of stabilized, detyrosinated microtubules, which are important for centrosome reorientation to the immunological synapse of T cells.

Cited by 77 publications

References 65 publications

Dynamic microtubules regulate cellular contractility during T-cell activation

Dynamic microtubules regulate cellular contractility during T-cell activation

Immune synapse: conductor of orchestrated organelle movement

Inverted formins: A subfamily of atypical formins

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