36 research outputs found
Fam65b Phosphorylation Relieves Tonic RhoA Inhibition During T Cell Migration
We previously identified Fam65b as an atypical inhibitor of the small G protein RhoA. Using a conditional model of a Fam65b-deficient mouse, we first show that Fam65b restricts spontaneous RhoA activation in resting T lymphocytes and regulates intranodal T cell migration in vivo. We next aimed at understanding, at the molecular level, how the brake that Fam65b exerts on RhoA can be relieved upon signaling to allow RhoA activation. Here, we show that chemokine stimulation phosphorylates Fam65b in T lymphocytes. This post-translational modification decreases the affinity of Fam65b for RhoA and favors Fam65b shuttling from the plasma membrane to the cytosol. Functionally, we show that the degree of Fam65b phosphorylation controls some cytoskeletal alterations downstream active RhoA such as actin polymerization, as well as T cell migration in vitro. Altogether, our results show that Fam65b expression and phosphorylation can finely tune the amount of active RhoA in order to favor optimal T lymphocyte motility
Caractérisation fonctionnelle de FINROD, un nouvel inhibiteur atypique des Rho GTPases dans l activation et la migration des lymphocytes T
Au cours de leur vie, les lymphocytes T subissent plusieurs changements phénotypiques importants: migration vers et à travers les organes lymphoïdes secondaires et passage d un état quiescent à un état activé. La migration et l activation sont régulées en partie par l activité des Rho GTPases, une famille de protéines impliquées dans la régulation de très nombreux processus biologiques. Nous avons identifié le produit du gène c6orf32 comme un partenaire des Rho GTPases. Cette protéine n est que peu décrite dans la littérature et ne présente aucun motif consensus. Par ailleurs, elle n avait fait l objet d aucune étude dans le système immunitaire. Nous avons montré que cette protéine agissait en tant qu inhibiteur des voies de signalisation contrôlées par la Rho GTPase RhoA. Le niveau d expression de c6orf32 affecte la capacité des cellules à répondre à un signal migratoire (activation de CCR7) ou activateur (engagement du TCR). L ampleur des réponses n est pas affectée, mais la taille de la sous-population répondeuse varie. Cette protéine contribue donc à fixer le seuil de sensibilité des cellules aux stimuli. Nous avons montré que l expression du gène c6orf32 était contrôlée par les facteurs de transcription FoxOs, dont l activité est réprimée au moment de l activation lymphocytaire. La présence du produit de c6orf32 est donc associée à un phénotype quiescent. Des approches biochimiques nous ont permis de montrer que la protéine codée par c6orf32 se fixait directement et diminuait la quantité de RhoA en conformation active présent dans les cellules. C est pourquoi nous avons baptisé cette protéine, FINROD (FoxOs-Induced RhoA Down-Modulator).In the course of their lifes, T cells undergo many phenotypic changes. They adopt a migratory behavior to and through secondary lymphoid organs, and switch upon infection from a resting to an activated state. Migration and activation are partly regulated by Rho GTPases. They form a family of proteins whose activity is crucial in the modulation of many biological processes. We have identified the c6orf32 gene product as a partner of Rho GTPases in human lymphocytes. This protein is barely described in the literature and does not display any consensus motifs. We have shown that this protein is an inhibitor of RhoA. The expression level of c6orf32 accordingly modulates the ability of T cells to respond to migratory cues (chemokines) or activation signals (TCR triggering). The magnitude of individual cellular responses is not affected; however, the protein participates in setting the threshold of response of RhoA-dependent pathways. Furthermore, we have shown that the c6orf32 gene was controlled by FoxOs transcription factors, whose activities are repressed after T lymphocytes activation. Therefore, the c6orf32-encoded protein is associated with a resting phenotype.Biochemical studies led us to discover that this protein directly binds to RhoA and subsequently diminishes the amount of active RhoA in cells. Thus, we decided to name it FINROD (FoxOs-induced RhoA Down-modulator).PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF
Rapid and Robust Analysis of Cellular and Molecular Polarization Induced by Chemokine Signaling
Une palmitoylation de CDC42 causée par une mutation déclenche un syndrome auto-inflammatoire sévère
International audienc
Activation of the Ancestral Polarity Regulator Protein Kinase Cζ at the Immunological Synapse Drives Polarization of Th Cell Secretory Machinery toward APCs
Specific activation of operculum 3 (OP3) brain region during provoked tinnitus-related phantom auditory perceptions in humans
International audienceThe phantom sound perception mechanism by which a sound perception occurs without any external sound source is still enigmatic. According to our previous fMRI study, a small region in the parietal operculum 3 was hyperactivated as a function of tinnitus periodicity in subjects with acoustic trauma tinnitus sequelae. This region was localized in the vicinity of neural correlates of middle-ear tympano-ossicular chain movements due to pressure variations. Disturbed proprioceptors are known to trigger illusory perceptions; therefore, we hypothesized that a disturbance of middle-ear proprioceptors may originate phantom sound perceptions. We designed an fMRI study that aimed to stimulate middle-ear proprioceptors by repetitive vibrations using various rates of click trains. In this study, we report that exposure to specific rates of stimuli for a few minutes at comfortable intensity level in healthy subjects distinctly triggered transient tinnitus-like aftereffects. The fMRI neural correlates of the aftereffects were unequivocally localized in the same parietal region as in acoustic trauma tinnitus sufferers. Our results strongly suggest that a middle-ear kinesthetic/proprioceptive illusion exists at the origin of acoustic trauma tinnitus via a somatosensory pathway encompassing the trigeminal system