Defective T cell development and function in<i>calcineurin</i>Aβ-deficient mice

Bueno, Orlando F.; Brandt, Eric B.; Rothenberg, Marc E.; Molkentin, Jeffery D.

doi:10.1073/pnas.152665399

Cited by 172 publications

(167 citation statements)

References 34 publications

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“…To study the role of calcineurin on Na/Pi-2 gene expression in vivo more directly, we used mice with genetic deletion of the calcineurin A␤ gene (calcineurin A␤ Ϫ/Ϫ ) (25). We first showed the expression of calcineurin A␤ in rat renal cortex.…”

Section: Resultsmentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

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Section: Resultsmentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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“…Calcineurin is located directly at this position in the TCR signaling cascade. Furthermore, calcineurin is unique for its activation by Ca 2+ /calmodulin as well as its ability to dephosphorylate cellular NFAT [5]. Fifth, NCI3 inhibits TCR-dependent NFAT and NF-jB signaling, which are both affected by calcineurin [25].…”

Section: Discussionmentioning

confidence: 99%

“…NFAT proteins are regulated by a reversible cycle of dephosphorylation and rephosphorylation. A TCR ligation-induced rise in intracellular free calcium levels triggers the activation of the Ca 2+ -calmodulin-dependent Ser/Thr-specific protein phosphatase calcineurin, which is unique in its property to dephosphorylate NFAT proteins [5]. Once activated, NFAT proteins translocate into the nucleus, bind to regulatory elements of NFAT target genes, interact with other nuclear proteins and control transcription.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of calcineurin‐NFAT signaling by the pyrazolopyrimidine compound NCI3

et al. 2007

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Dephosphorylation of NFAT by the Ca 2+ -calmodulin-dependent Ser/Thr protein phosphatase calcineurin is a bottleneck of T cell receptor-dependent activation of T cells. In dimeric complexes with immunophilins, the immunosuppressants cyclosporine A (CsA) and tacrolimus (FK506) block this process by inhibition of the enzymatic activity of calcineurin. We have identified the pyrazolopyrimidine compound NCI3 as a novel inhibitor of calcineurin-NFAT signaling. Similar to CsA and FK506, NCI3 inhibits dephosphorylation and nuclear translocation of NFAT, IL-2 production and proliferation of stimulated human primary T cells with IC 50 values from 2 to 4.5 lM. However, contrary to CsA and FK506, NCI3 neither blocks calcineurin`s phosphatase activity nor requires immunophilins for inhibiting NFAT activation. Our data suggest that NCI3 binds to calcineurin and causes an allosteric change interfering with NFAT dephosphorylation in vivo but not in vitro. NCI3 acts not only on the endogenous calcineurin but also on a C-terminally truncated, constitutively active version of calcineurin. The novel inhibitor described herein will be useful in better defining the cellular regulation of calcineurin activation and may serve as a lead for the development of a new type of immunosuppressants acting not by direct inhibition of the calcineurin phosphatase activity.

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“…in T cell resulted in a reduced cell numbers of SP thymocytes and a defect of peripheral T cell activation (33). It was reported that NFAT1 and NFAT2 can be directly SUMOylated, and SUMOylation modification regulates their transcriptional activities by promoting their nuclear anchorage within nuclear bodies (42,43).…”

Section: Tcr-induced Nfat Nuclear Localization Is Regulated By Sumoylmentioning

confidence: 99%

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional roles of SUMOylation in T cell development. Loss of Ubc9 results in a significant reduction of CD4 and CD8 single-positive lymphocytes in both thymus and periphery. Ubc9-deficient cells exhibit defective late-stage maturation post the initial positive selection with increased apoptosis and impaired proliferation, among which attenuated IL-7 signaling was correlated with the decreased survival of Ubc9-deficent CD8 single-positive cells. Furthermore, NFAT nuclear retention induced by TCR signals was regulated by SUMOylation during thymocytes development. Our study thus reveals a novel posttranslational mechanism underlying T cell development.

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Defective T cell development and function incalcineurinAβ-deficient mice

Cited by 172 publications

References 34 publications

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Inhibition of calcineurin‐NFAT signaling by the pyrazolopyrimidine compound NCI3

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

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