Phosphatase PP2A is requisite for the function of regulatory T cells

Apostolidis, Sokratis A.; Rodríguez-Rodríguez, Noé; Suárez‐Fueyo, Abel; Dioufa, Nikolina; Özcan, Esra; Crispín, José C.; Tsokos, Maria; Tsokos, George C.

doi:10.1038/ni.3390

Cited by 202 publications

(225 citation statements)

References 56 publications

Supporting

Mentioning

218

Contrasting

Order By: Relevance

“…Indeed, PP2A signaling was recently shown to be crucial for Treg function. The catalytic activity of PP2A in Tregs from mice was reported to be increased at levels significantly higher than in conventional Tconv cells [58]. In this study, mice deficient in PP2Ac Tregs developed spontaneously severe, progressive, multi-organ autoimmunity characterized by wasting, dermatitis, scaly tails and ears, eyelid crusting and in some occasions overt skin rash and ulcerations.…”

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 61%

“…Novel Treg-specific mechanisms relying on environmental and cytosolic cues to restrain mTORC1 have recently been described, and one example is protein phosphatase 2A (PP2A) [58]. Indeed, PP2A signaling was recently shown to be crucial for Treg function.…”

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 99%

“…T cells were activated in all lymphoid organs and produced IL-17, while multiple autoantibodies were detected in the serum. Activation of PP2A required the presence of ceramide, and Foxp3 expression led to PP2A accumulation by inhibiting the gene sgms1 , whose product is ceramide degrading enzyme sphingomyelinase synthase 1 [58]. Of note, functional Tregs contain high amounts of ceramides, and PP2Ac was demonstrated to inactivate mTORC1 without affecting mTORC2 and PI(3)K/Akt pathways (Figure2).…”

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 99%

See 2 more Smart Citations

Empowering Regulatory T Cells in Autoimmunity

Kasper

Apostolidis

Sharabi

et al. 2016

Trends in Molecular Medicine

View full text Add to dashboard Cite

Regulatory T cells (Tregs) are capable of dampening immune-mediated inflammation and avert the destructive effects of uncontrolled inflammation. Distinct molecules and pathways, including various transcription factors, phosphatases and kinases, impact the ability of Tregs to function as negative regulators of the immune response, and are presumably amenable to therapeutic manipulation. Here, we discuss recently identified molecular networks and the therapeutic potential for treating autoimmune diseases.

show abstract

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 61%

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 99%

Section: Known Molecular Requirements For Treg Sustenance and Functionmentioning

confidence: 99%

See 1 more Smart Citation

Empowering Regulatory T Cells in Autoimmunity

Kasper

Apostolidis

Sharabi

et al. 2016

Trends in Molecular Medicine

View full text Add to dashboard Cite

show abstract

“…A previous study has demonstrated that PP2A inhibition also re-established the metabolic profile of Treg cells in PP2A flox mice [37]. These authors showed that the transgenic knockdown of PP2A resulted in augmented glycolytic activity and mitochondrial respiratory capacity in the PP2A flox Tregs.…”

Section: Discussionmentioning

confidence: 88%

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

Liu¹,

Wang²,

Cui³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma. Methods: In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting. Results: The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus. Conclusion: These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment.

show abstract

“…[10][11][12][13][14][15] The recent observation, that CRP formation is essential in controlling the metabolic activity of regulatory T cells demonstrates that ceramides play also an essential role in regulating immune functions and inflammation. [16,17] However, despite these important roles the molecular organization of ceramides in the plasma membrane remains elusive. Hitherto, CRPs have been studied extensively in artificial membranes by biochemical and biophysical approaches [3,4,[18][19][20] and in fixed cells by immunocytochemistry.…”

Section: Graphical Abstractmentioning

confidence: 99%

Characterization of Plasma Membrane Ceramides by Super‐Resolution Microscopy

Burgert

Schlegel

Bécam³

et al. 2017

Angewandte Chemie

View full text Add to dashboard Cite

The sphingolipid ceramide regulates cellular processes such as differentiation, proliferation, growth arrest and apoptosis. Ceramide-rich membrane areas promote structural changes within the plasma membrane which segregates membrane receptors and affect membrane curvature and vesicle formation, fusion and trafficking. Here, we label ceramides by immunocytochemistry and visualize their distribution on the plasma membrane of different cells with virtually molecular resolution by direct stochastic optical reconstruction microscopy (dSTORM). Super-resolution images show that independent of labeling conditions and cell type 50-60% of all membrane ceramides are located in ceramide-rich platforms (CRPs) with a size of ~ 75 nm which are composed of at least ~ 20 ceramides. Treatment of cells with Bacillus cereus sphingomyelinase (bSMase) increases the overall ceramide concentration in the plasma membrane, the quantity of CRPs and their size. Simultaneously, the ceramide concentration in CRPs increases approximately twofold. Graphical Abstractd STORM reveals that independent of the cell type membrane ceramides form nanodomains (CRPs) with a diameter of ~ 75 nm containing 50-60% of all ceramides. Treatment with sphingomyelinase increases the quantity of ceramides, the size and density of CRPs as well as the ceramide concentration in CRPs.Correspondence to: Markus Sauer. Supporting information for this article is given via a link at the end of the document. The plasma membrane is mainly composed of glycerophospholipids, sphingolipids and cholesterol. Sphingolipids are natural lipids comprised of the sphingoid base backbone sphingosine, which when N-acylated with fatty acids forms ceramide, a central molecule in sphingolipid biology. De-novo synthesis of ceramide occurs in the endoplasmatic reticulum followed by conversion into complex sphingolipids in the Golgi apparatus. In addition, sphingomyelinases (SMases) can generate ceramide from sphingomyelin in the plasma membrane. [1,2] Interactions of sphingolipids with one another and with cholesterol typically result in membrane microdomains or 'rafts' which segregate membrane-associated proteins and compartmentalize signaling components within the plasma membrane. [3][4][5][6] Activation of SMases by cellular stress or ligation of receptors results in ceramide synthesis and subsequent self-association within the plasma membrane resulting in ceramide-rich platforms (CRPs). [7,8] The formation of CRPs rearranges the organization of the plasma membrane including clustering of diverse receptors and facilitates vesicle formation and fusion. [8,9] These changes induce differentiation, proliferation, growth arrest, and cell death. [1,2] Moreover, SMases and ceramides have been shown to be critically involved in the internalization of pathogens. [10][11][12][13][14][15] The recent observation, that CRP formation is essential in controlling the metabolic activity of regulatory T cells demonstrates that ceramides play also an essential role in regulating immune functions and i...

show abstract

Phosphatase PP2A is requisite for the function of regulatory T cells

Cited by 202 publications

References 56 publications

Empowering Regulatory T Cells in Autoimmunity

Empowering Regulatory T Cells in Autoimmunity

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

Characterization of Plasma Membrane Ceramides by Super‐Resolution Microscopy

Contact Info

Product

Resources

About