Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells

Srivastava, S. K.; Ko, Kyung Ae; Choudhury, Papiya; Zhai, Li; Johnson, A.; Nadkarni, Vivek; Unutmaz, Derya; Coetzee, William A.; Skolnik, Edward Y.

doi:10.1128/mcb.00352-06

Cited by 47 publications

(61 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, these findings, together with the demonstration that PI3KC2β enzyme activity is increased in TRIM27 −/− lymphocytes, supports a model whereby direct ubiquitination of PI3KC2β by TRIM27 results in the inhibition of PI3KC2β's enzymatic activity leading to decreased levels of PI3P, resulting in decreased histidine phosphorylation and activation of KCa3.1 by NDPK-B (Fig. S7) (19,40,41,47).…”

Section: Th1supporting

confidence: 51%

See 1 more Smart Citation

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Cai

Srivastava

Sun

et al. 2011

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

Self Cite

View full text Add to dashboard Cite

The K + channel KCa3.1 is required for Ca 2+ influx and the subsequent activation of CD4 T cells. The class II phosphatidylinositol 3 kinase C2β (PI3KC2β) is activated by the T-cell receptor (TCR) and is critical for KCa3.1 channel activation. Tripartite motif containing protein 27 (TRIM27) is a member of a large family of proteins that function as Really Interesting New Gene (RING) E3 ubiquitin ligases. We now show that TRIM27 functions as an E3 ligase and mediates lysine 48 polyubiquitination of PI3KC2β, leading to a decrease in PI3K enzyme activity. By inhibiting PI3KC2β, TRIM27 also functions to negatively regulate CD4 T cells by inhibiting KCa3.1 channel activity and TCR-stimulated Ca 2+ influx and cytokine production in Jurkat, primary human CD4 T cells, and Th0, Th1, and Th2 CD4 T cells generated from TRIM27 −/− mice. These findings provide a unique mechanism for regulating class II PI3Ks, and identify TRIM27 as a previously undescribed negative regulator of CD4 T cells.

show abstract

Section: Th1supporting

confidence: 51%

“…Whole-cell patch clamping on activated CD4 T cells (47) and Jurkat-KCa3.1 T cells, PI3P rescue experiment and Ca 2+ imaging were performed as previously described (19) and detailed in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Cai

Srivastava

Sun

et al. 2011

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…KCa3.1 is expressed at low levels in resting naïve CD4 T cells and is transcriptionally activated following TCR stimulation, leading to increased numbers of KCa3.1 channels in activated cells (10,30,31). We found that KCa3.1 channel activity is also markedly up-regulated following differentiation into Th1 and Th2 cells, and KCa3.1 accounts for the majority of the K + current in these cells.…”

Section: Discussionmentioning

confidence: 63%

“…Whole-cell patch-clamping was performed on activated CD4 T cells 48 h after stimulation with anti-CD3 and anti-CD28 antibodies as described (19) with some modification (30).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Srivastava

Zhdanova

et al. 2010

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

Self Cite

140

138

View full text Add to dashboard Cite

The calcium-activated K + channel KCa3.1 plays an important role in T lymphocyte Ca 2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1 −/− mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1 −/− mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor–stimulated Ca 2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca 2+ influx and cytokine production were impaired in KCa3.1 −/− Th1 and Th2 CD4 T cells, whereas T-regulatory and Th17 function were normal. We found that inhibition of KCa3.1 −/− protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by ( i ) the adoptive transfer of mouse naïve CD4 T cells into rag2 −/− recipients and ( ii ) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

show abstract

“…MTMR6, a member of the myotubularin family of 3Ј-phosphatases with specificity for PtdIns(3)P and PtdIns(3,5)P 2 ( Fig. 1), binds the K Ca 3.1 calcium-activated potassium channel through coiledcoil domain interaction (49). The K Ca 3.1 channel is essential in the maintenance of the membrane potential that drives Ca 2ϩ influx during activation of naive and memory CD4 ϩ T cells.…”

Section: Evidence For a Role Of Other Lipid Phosphatases In T Lymphocmentioning

confidence: 99%

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Harris

Parry

Westwick

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The phosphoinositide 3-kinase signaling pathway has been implicated in a range of T lymphocyte cellular functions, particularly growth, proliferation, cytokine secretion, and survival. Dysregulation of phosphoinositide 3-kinase-dependent signaling and function in leukocytes, including B and T lymphocytes, has been implicated in many inflammatory and autoimmune diseases. As befits a pivotal signaling cascade, several mechanisms exist to ensure that the pathway is tightly regulated. This minireview focuses on two lipid phosphatases, viz. the 3 -phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SHIP (Src homology 2 domain-containing inositol-5-phosphatase). We discuss their role in regulating T lymphocyte signaling as well their potential as future therapeutic targets.The PI3K 3 pathway plays a central role in regulating many biological processes, primarily via the generation of the potent second messenger PtdIns(3,4,5)P 3 , which acts as a docking site at the plasma membrane, recruiting and activating proteins containing pleckstrin homology (PH) domains (1). These downstream PI3K effectors include PDK-1 (3Ј-phosphoinositide-dependent kinase-1), which phosphorylates and activates the AGC protein kinases, including protein kinase B/Akt. Other kinases such as Tec family kinases can also interact directly with PtdIns(3,4,5)P 3 , as can GTPase-activating proteins and guanine nucleotide exchange factors as well as scaffolding proteins that nucleate the assembly of key signaling complexes (1, 2). PI3K and T LymphocytesT cells express all three class 1A PI3K isoforms (p110␣, p110␤, and p110␦), which are regulated by protein-tyrosine kinase-coupled receptors, as well as class 1B p110␥, which is activated by G protein-coupled receptors (GPCRs). The T cell antigen receptor (TCR), CD28 family co-stimulatory receptors, and cytokine receptors activate class 1A isoforms (3). Chemokines (by virtue of interacting with GPCRs), activate mainly class 1B PI3K (4). Use of pharmacological tools in leukemic human T cell lines first indicated a possible role for PI3K in T cell activation (5). Mice with a knock-in point mutation of p110␦ that abolishes kinase activity exhibit selective impairments in TCR signaling and reduced proliferation in vitro (6) and impaired function of CD4 ϩ CD25 ϩ Foxp3 ϩ T Reg cells (7). Interestingly, mice lacking both p110␥ and p110␦ show much more profound defects in thymocyte development and survival compared with mice lacking individual isoforms, indicating that these isoforms serve partially redundant functions in thymocytes (8, 9). Pathological consequences of combined p110␥␦ deficiency includes T cell lymphopenia, which leads to multiple-organ inflammation (10). Surprisingly, mice with T cellspecific loss of class 1A PI3K exhibit largely normal thymocyte development, and peripheral T cell numbers and subsets are unimpaired in young animals (11,12). In vitro proliferation of T cells from these mice in response to TCR ligation is abrogated, and there is complete loss of PI3K sig...

show abstract

Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells

Cited by 47 publications

References 30 publications

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Contact Info

Product

Resources

About

Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells

Cited by 47 publications

References 30 publications

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Inhibition of the K+channel KCa3.1 ameliorates T cell–mediated colitis

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Contact Info

Product

Resources

About

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis