Background It is known that retinoid receptor function is attenuated during

Background It is known that retinoid receptor function is attenuated during T cell activation, a phenomenon that involves actin remodeling, suggesting that actin changes may play a role in such inhibition. receptor-dependent transcription. Further evidence of the role of LMK1/CFL1-mediated actin mechanics, was provided by studying the effect of Nef, an actin changing HIV-1 protein, on receptor function. Manifestation of Nef induced phosphorylation of CFL1 at serine 3 and LIMK1 at threonine 508, inhibited retinoid-receptor mediated reporter activity, and the manifestation of a number of genes that contain retinoid receptor binding sites in their promoters. The results suggest that the Nef-mediated inhibition of receptor function encompasses deregulation of actin filament mechanics by LIMK1 activation and phosphorylation of CFL1. Conclusion We have recognized a crucial role of LIMK1-mediated CFL1 pathway and actin mechanics in modulating retinoid receptor mediated function and shown that LIMK1-mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity. We suggest that T cell activation-induced repression of nuclear receptor-dependent transactivation is usually in part through the changes of actin mechanics. Background Nuclear retinoid receptors are retinoid-induced transcription factors that mediate a wide array of cellular functions including growth, differentiation, and cell death. While the role of these receptors in immune function has been acknowledged early, it is usually only recently that retinoids have been recognized to play a crucial role in T lymphocyte physiology like regulatory T cell development and suppression of inflammatory Th17 cells [1-4]. Our understanding of the mechanism of retinoid receptor function in T cells is however, not well defined. Our previous studies have provided some insights in the functioning of these receptors and have identified the relevance of epigenetic mechanisms in modulating their function during T cell signaling [5-9]. A major signaling event during T cell activation is the organization of the actin cytoskeleton and immunological synapse (IS) formation. These events are crucial for downstream signaling that culminates in effector functions and cytokine production [10,11]. Recent studies have identified CFL1, an actin binding protein, as an essential component of T cell activation that is crucial for IS formation and T cell activation. Most of the CFL1 in naive T cells is found in the inactive phosphorylated form that following TCR activation, involving accessory receptors, is dephosphorylated into an active form [10,12,13]. KILLER The active form of CFL1 binds actin and regulates F-actin dynamics. Serine/threonine kinase LIMK1 and phosphatases PP1, PP2A, slingshot 1L (SSH1L), and chronophin (CIN) are known to regulate the phosphorylated state of CFL1 [14-16]. HIV-1 gains entry into T cells by the interaction of viral proteins with receptors and co-receptors. This interaction leads to the perturbation in actin dynamics and viral replication. Recent studies have identified CFL1 as a central player in regulating the modification of the actin cytoskeleton by HIV-1 proteins gp120 and Nef [17-21]. Nef is known to interact with actin and modify actin cytoskeletal dynamics and the T cell receptor initiated signaling cascade. Nef has been also shown to inhibit IS formation and cell spreading by modifying actin function [22,23]. There is ample evidence that actin plays a functional role in nuclear Miriplatin hydrate transcription and disturbances in actin Miriplatin hydrate dynamics affect transcriptional outcome [24-32]. We have reported earlier that T cell activation silenced transcription driven by nuclear retinoid receptors and induced silencing mediator of retinoic acid and thyroid hormone receptors (SMRT)-receptor interaction (6). We also identified a dynamic balance between JNK and ERK pathways in modulating retinoid-receptor function (8). The mechanism by which T cell activation induces loss of transcription is still not completely understood. In this report we have focused our studies to investigate the role of actin cytoskeleton homeostasis and dynamics in nuclear retinoid receptor-mediated transactivation. Our results indicate a critical role of LIMK1-mediated CFL1 pathway and actin dynamics Miriplatin hydrate in retinoid receptor function. The data. Miriplatin hydrate

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