Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation

Gibson, Sara A.; Yang, Wei; Yan, Zhaoqi; Liu, Yudong; Rowse, Amber L.; Weinmann, Amy S.; Qin, Hongwei; Benveniste, Etty N.

doi:10.4049/jimmunol.1601912

Cited by 41 publications

(65 citation statements)

References 48 publications

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“…This was not cell type-dependent, since a CX-4945-induced reduction of pS473 Akt, besides pT308, was repeatedly reported by us and other groups (e.g. [40,[42][43][44][45] and was also observed in C2C12 (S1C Fig) and in GN11 (not shown) cells, where we found that CK2β knock out caused instead an increased pS473 level. The reduction of pS473 by CX-49445 was observed also in shCK2β, suggesting that its increase due to CK2β downregulation requires the presence of active CK2 (see Discussion).…”

Section: Ck2β Depletion In the Renal Cell Line Hk-2 Unbalances P-akt(supporting

confidence: 85%

Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

et al. 2020

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The PI3K/Akt pathway is interconnected to protein kinase CK2, which directly phosphorylates Akt1 at S129. We have previously found that, in HK-2 renal cells, downregulation of the CK2 regulatory subunit β (shCK2β cells) reduces S129 Akt phosphorylation. Here, we investigated in more details how the different CK2 isoforms impact on Akt and other signaling pathways.We found that all CK2 isoforms phosphorylate S129 in vitro, independently of CK2β. However, in HK-2 cells the dependence on CK2β was confirmed by rescue experiments (CK2β re-expression in shCK2β HK-2 cells), suggesting the presence of additional components that drive Akt recognition by CK2 in cells. We also found that CK2β downregulation altered the phosphorylation ratio between the two canonical Akt activation sites (pT308 strongly reduced, pS473 slightly increased) in HK-2 cells. Similar results were found in other cell lines where CK2β was stably knocked out by CRISPR-Cas9 technology. The phosphorylation of rpS6 S235/S236, a downstream effector of Akt, was strongly reduced in shCK2β HK-2 cells, while the phosphorylation of two Akt direct targets, PRAS40 T246 and GSK3β S9, was increased. Differently to what observed in response to CK2β down-regulation, the chemical inhibition of CK2 activity by cell treatment with the specific inhibitor CX-4945 reduced both the Akt canonical sites, pT308 and pS473. In CX-4945-treated cells, the changes in rpS6 pS235/S236 and GSK3β pS9 mirrored those induced by CK2β knockdown (reduction and slight increase, respectively); on the contrary, the effect on PRAS40 pT246 phosphorylation was sharply different, being strongly reduced by CK2 inhibition; this suggests that this Akt target might be dependent on Akt pS473 status in HK-2 cells.Since PI3K/Akt and ERK1/2/p90rsk pathways are known to be interconnected and both modulated by CK2, with GSK3β pS9 representing a convergent point, we investigated if ERK1/2/p90rsk signaling was affected by CK2β knock-down and CX-4945 treatment in HK-PLOS ONE | https://doi.

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Section: Ck2β Depletion In the Renal Cell Line Hk-2 Unbalances P-akt(supporting

confidence: 85%

Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

et al. 2020

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“…In this context, pharmacological inhibition, or genetic silencing of CK2 in CD4 T cells leads to increased Treg generation and decreased Th17 differentiation, possibly as a result of lower STAT3 phosphorylation and the inhibition of the PI3K/AKT/mTOR pathways (Fig. ) . As CK2 is constitutively associated with CD5, the role of CD5 in T cell differentiation has been recently addressed.…”

Section: Cd5 As Regulator Of Th Differentiationmentioning

confidence: 99%

The multiple faces of CD5

Burgueño‐Bucio

Mier‐Aguilar

Soldevila

2019

Journal of Leukocyte Biology

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Since its discovery, over 30 years ago, CD5 has been used as a marker to identify T cells, B1‐a cells, and B cell chronic lymphocytic leukemia cells. Throughout the years, many studies have described the functional relevance of CD5 as a modulator of T and B cell receptor signaling. However, it has not been until recent years that CD5 has emerged as a functional receptor in other areas of the immune system. Here, we review some of the most important aspects of CD5 as a modulator of TCR and BCR signaling, cell survival receptor both in T and B cells during health and disease, as well as the newly discovered roles of this receptor in thymocyte selection, T cell effector differentiation, and immune tolerance. CD5 was found to promote T cell survival by protecting autoreactive T cell from activation‐induced cell death, to promote de novo induction of regulatory T cells in the periphery, to modulate Th17 and Th2 differentiation, and to modulate immune responses by modulating dendritic cell functions. CD5 is overexpressed in Tregs and Bregs, which are fundamental to maintain immune homeostasis. The newly established roles of CD5 in modulating different aspects of immune responses identify this receptor as an immune checkpoint modulator, and therefore it could be used as a target for immune intervention in different pathologies such as cancer, autoimmune diseases or infections.

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“…Of note, we also detected genes that promote pro-inflammatory T cells. For example, CKS2, LDHA, and LDHB, promote Th17 differentiation ( 83, 84 ), and Th1 T eff cells ( 85 ), respectively. LDHA is induced by T cell activation to support aerobic glycolysis, however, it also promotes IFNγ production via enhanced histone acetylation through acetyl-CoA ( 85 ).…”

Section: Resultsmentioning

confidence: 99%

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

Pompura

Wagner

Kitz

et al. 2020

Preprint

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25FoxP3 positive regulatory T cells (T regs ) rely on fatty acid b-oxidation (FAO)-driven OXPHOS for 26 differentiation and function. Recent data have demonstrated a role for T regs in the maintenance of 27 tissue homeostasis with tissue-resident T regs possessing tissue-specific transcriptomes. However, 28 specific signals that establish these tissue-resident T regs programs are largely unknown. As T regs 29 metabolically rely on FAO, and considering the lipid-rich environments of tissues, we 30 hypothesized that environmental lipids drive T reg homeostasis. Using human adipose tissue as a 31 model for tissue residency, we identify oleic acid as the most prevalent free fatty acid in human 32 adipose tissue. Mechanistically, oleic acid amplifies T reg FAO-driven OXPHOS metabolism, 33 creating a positive feedback mechanism that induces the expression of Foxp3 and enhances 34 phosphorylation of STAT5, which acts to stabilize the T reg lineage and increase suppressive 35 function. Comparing the transcriptomic program induced by oleic acid to that of the pro-36 inflammatory arachidonic acid, we find that T regs sorted from peripheral blood and adipose of 37 healthy donors transcriptomically resemble the oleic acid in vitro treated T regs , whereas T regs 38 obtained from the adipose tissue of relapsing-remitting MS patients more closely resemble an 39 arachidonic acid profile. Finally, we find that oleic acid concentrations are reduced in the fat tissue 40 of MS patients, and exposure of dysfunctional MS T regs to oleic acid restores defects in their 41 suppressive function. These data demonstrate the importance of fatty acids in regulating tissue 42 inflammatory signals. 43 44 45 Metabolic signatures of T cells are intricately linked to their differentiation and activation 46 status. Metabolic pathways facilitate cellular functions, therefore linking metabolic remodeling to 47 the development, activation, differentiation, and survival of T cells. Upon activation, quiescent, 48 naïve T cells become rapidly dividing effector T (T eff ) cells and switch their metabolic program 49 from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, known as the Warburg effect, in 50order to meet the increase in demand for cellular energy and biomass (1, 2). However, despite 51 having similar developmental origins, regulatory T cells (T regs ) rely predominantly on a fatty acid 52 b-oxidation (FAO)-driven OXPHOS metabolic program to maintain their suppressive phenotype, 53 which is further promoted by the expression of FoxP3 (3-5). Forced expression of FoxP3 in T cells 54 suppresses glycolysis-related genes while inducing lipid and oxidative metabolic-related genes 55 that are required for maximum suppression (4). In addition, cytokines that promote T reg 56 differentiation, such as TGF-b (6), activate AMPK (7) and promote FAO to skew naïve T cells into 57 a T reg phenotype (3, 8). Furthermore, T reg differentiation and suppression are reduced by inhibiting 58 FAO (3), highlighting the importance of FAO-driven OXPHOS in the in...

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Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation

Cited by 41 publications

References 48 publications

Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

The multiple faces of CD5

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

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