Calcium signaling in lymphocytes

Oh‐hora, Masatsugu; Rao, Anjana

doi:10.1016/j.coi.2008.04.004

Cited by 352 publications

(294 citation statements)

References 78 publications

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“…PKC are activated by the phospholipase C (PLC)-g enzymes, which are enriched in leukocytes and mediate conversion of phosphoinositide (4,5) bisphosphate (PIP 2 ) into inositol (1,4,5) trisphosphate (IP 3) and diacylglycerol. Consequently, the generation of IP 3 leads to intracellular Ca 21 release from the endoplasmic reticulum, which along with diacylglycerol production leads to the activation of cPKC [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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Conventional PKC (cPKC)-a regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-a is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö 6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-a repressed Pam 3 CSK 4 induced NF-jB-and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-jB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-a À/À mice exhibited decreased TNF-a and IL-12p40 production induced by both MyD88-and TRIF-dependent ligands. Furthermore, PKC-a is coupled to TLR2 signaling proximal to MyD88 since MAPK and IjB kinase-a/b phosphorylations and IjBa degradation were inhibited in PKC-a À/À BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-a physically interacts with Pam 3 CSK 4 activated TLR2 in WT but not in MyD88 À/À DC. Collectively this study identifies a species-specific role of PKC-a as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.Key words: MyD88 . PKC . TLR Supporting Information available online Introduction TLR are a family of evolutionary conserved transmembrane proteins that are expressed on numerous cell types including Mf and DC. They function as pathogen recognition receptors, sensing a wide range of invading pathogens including bacteria, fungi and viruses through recognition of PAMP. Engagement of TLR by microbial products triggers the activation of two distinct signaling pathways: the MyD88-dependent and -independent pathways, Ã These authors contributed equally to this work.ÃÃ These authors contributed equally to this work. [4,5]. Recent studies identified several PKC isoforms as key regulators of TLR signaling pathways. PKC serine/threonine kinase family is classified into three groups according to their structure homology and co-factor regulation (conventional PKC (a, bI, bII, and g), novel PKC (d, e, y and Z/L) and atypical PKC (l/i and z)) [6,7]. PKC-e À/À Mf display a major defect in their ability to generate inflammatory mediators in response to LPS and are highly susceptible to Gram-positive and Gram-negative infections [8,9]. PKC-e is also involved in LPS-induced MAPK phosphatase 1 expression in MF and plays a critical role in LPS-induced IL-12p70 and TNF-a production in DC [10,11]. PKC-e À/À and PKC-d À/À MF display an impaired activation of NF-kB and MAPK downstream of TLR2 and TLR4 [8,12]. PKC-d is necessary to induce Stat-1 activation in response to LPS in murine MF [13]. PKC-z is implicated in LPS-induced MAPK and NF-kB...

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Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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“…Calcium binds to calmodulin, which in turn activates the calmodulin-dependent phosphatase calcineurin. NFAT proteins are then dephosphorylated by activated calcineurin, an event that leads to their nuclear translocation and initiation of NFAT-mediated gene transcription [30]. Because PLCg2 is a master regulator of calcium flux downstream of ITAM-containing receptors, we first asked whether the generation of IL-2 and COX-2 transcripts was affected by the lack of PLCg2.…”

Section: Dectin-1 Requires Plcc2 For Ap-1 Nf-jb and Nfat Activationmentioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

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DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T-cell responses. Dectin-1 is a PRR that recognizes b-glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin-1 activates DC through phospholipase (PLC)c2 signaling. PLCc2-deficient DC were unable to expand antigen-specific T cells and induce T H 1 and T H 17 differentiation in response to b-glucan. Mechanistically, PLCc2-deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to b-glucan. Dectin-1 required PLCc2 to activate MAPK, AP-1 and NF-jB, which induce cytokine gene expression. Moreover, PLCc2 controlled Dectin-1-mediated NFAT activation and induction of NFAT-dependent genes such as IL-2, cyclooxigenase-2 and Egr transcription factors. We conclude that PLCc2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to b-glucan-containing pathogens.Key words: DC . Dectin-1 . PLCg . Signaling Supporting Information available online Introduction DC play a key role in gathering information from the surrounding environment and initiating appropriate immune responses when needed [1,2]. Because they bridge innate and adaptive immunity, DC are equipped with a multitude of intracellular and cell surface receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, collectively known as PRR, include TLR [3], C-type lectins such as Dectin-1 [4], scavenger receptors [5], the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the NOD-like receptors and the RIG-like receptors [6].Dectin-1 recognizes b-glucan, a major constituent of many fungi's outer cell wall [4,7] and triggers intracellular signals through a cytoplasmic tyrosine motif resembling the ITAM. Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for [20,21]. Syk, together with the tyrosine kinases BTK and Src, activate PLCg through tyrosine phosphorylation [22]. Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.PLCg includes two isoforms, PLCg1 and PLCg2, which hydrolyze membrane phosphatidylinositol 4,5-biphosphate into inositol 1,4,5-trisphosphate and diacylglicerol (DAG) [20]. Inositol 1,4,5-trisphosphate triggers the ...

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“…Calcium signaling in T-cell biology is well characterized [16,17]. TCR engagement couples to PLCg1-dependent synthesis of inositol 3-phosphate.…”

Section: Transcriptional Regulation Of E3 Ligases In T-cell Tolerancementioning

confidence: 99%

“…TCR engagement couples to PLCg1-dependent synthesis of inositol 3-phosphate. Inositol 3-phosphate promotes the release of calcium from the endoplasmic reticulum into the cytosol, which in turn, opens the calcium release activated channels at the plasma membrane [16,17]. The sustained influx of extracellular Ca 21 through calcium release activated channels (CARC) activates the phosphatase calcineurin, which subsequently binds and dephosphorylates the cytosolic NFAT family of transcription factors.…”

Section: Transcriptional Regulation Of E3 Ligases In T-cell Tolerancementioning

confidence: 99%

“…Early studies revealed that anergy does not constitute a simple loss of signaling molecules, but an active process where ''anergic factors'' are being synthesized to establish and maintain the unresponsive state [11,14]. Subsequently, genome wide screening analysis further confirmed the differential transcriptional profile between anergic and activated T cells, and identified the calcium/NFAT signaling pathway as a key pathway for the induction of at least one genetic program associated with T-cell anergy [15].Calcium signaling in T-cell biology is well characterized [16,17]. TCR engagement couples to PLCg1-dependent synthesis of inositol 3-phosphate.…”

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E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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Calcium signaling in lymphocytes

Cited by 352 publications

References 78 publications

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

E3 ubiquitin ligases in T‐cell tolerance

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Calcium signaling in lymphocytes

Cited by 352 publications

References 78 publications

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

E3 ubiquitin ligases in T‐cell tolerance

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Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization