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See detailStress hormone signalling inhibits Th1 polarization in a CD4 T-cell-intrinsic manner via mTORC1 and the circadian gene PER1
Capelle, Christophe M.; Chen, Anna; Zeng, Ni et al

in Immunology (2022), 165(4), 428--444

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that ... [more ▼]

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that both adrenergic- and glucocorticoid-mediated stress signalling pathways play a CD4 naïve T-cell-intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell-autonomous mechanism connects stress hormone signalling with CD4 T-cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1. [less ▲]

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See detailDJ-1 depletion slows down immunoaging in T-cell compartments
Zeng, Ni; Capelle, Christophe; Baron, Alexandre et al

Report (2021)

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance ... [more ▼]

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7 /DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly delayed immunoaging in both human and mice. Compared with two gender-matched unaffected sibling carriers of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled frequencies of non-senescent T cells. The observation of a ‘younger’ immune system in the index patient was further consolidated by the results in aged DJ-1 knockout mice. Our data from bone marrow chimera models and adoptive transfer experiments demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases. [less ▲]

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See detailL-plastin Ser5 phosphorylation is modulated by the PI3K/SGK pathway and promotes breast cancer cell invasiveness
Machado, Raquel A.C.; Stojevski, Dunja; de Landtsheer, Sébastien UL et al

in Cell Communication and Signaling (2021), 19(22), 1-22

Background: Metastasis is the predominant cause for cancer morbidity and mortality accounting for approxima‑ tively 90% of cancer deaths. The actin‑bundling protein L‑plastin has been proposed as a ... [more ▼]

Background: Metastasis is the predominant cause for cancer morbidity and mortality accounting for approxima‑ tively 90% of cancer deaths. The actin‑bundling protein L‑plastin has been proposed as a metastatic marker and phos‑ phorylation on its residue Ser5 is known to increase its actin‑bundling activity. We recently showed that activation of the ERK/MAPK signalling pathway leads to L‑plastin Ser5 phosphorylation and that the downstream kinases RSK1 and RSK2 are able to directly phosphorylate Ser5. Here we investigate the involvement of the PI3K pathway in L‑plastin Ser5 phosphorylation and the functional effect of this phosphorylation event in breast cancer cells. Methods: To unravel the signal transduction network upstream of L‑plastin Ser5 phosphorylation, we performed computational modelling based on immunoblot analysis data, followed by experimental validation through inhi‑ bition/overexpression studies and in vitro kinase assays. To assess the functional impact of L‑plastin expression/ Ser5 phosphorylation in breast cancer cells, we either silenced L‑plastin in cell lines initially expressing endogenous L‑plastin or neoexpressed L‑plastin wild type and phosphovariants in cell lines devoid of endogenous L‑plastin. The established cell lines were used for cell biology experiments and confocal microscopy analysis. Results: Our modelling approach revealed that, in addition to the ERK/MAPK pathway and depending on the cellular context, the PI3K pathway contributes to L‑plastin Ser5 phosphorylation through its downstream kinase SGK3. The results of the transwell invasion/migration assays showed that shRNA‑mediated knockdown of L‑plastin in BT‑20 or HCC38 cells significantly reduced cell invasion, whereas stable expression of the phosphomimetic L‑plastin Ser5Glu variant led to increased migration and invasion of BT‑549 and MDA‑MB‑231 cells. Finally, confocal image analysis combined with zymography experiments and gelatin degradation assays provided evidence that L‑plastin Ser5 phosphorylation promotes L‑plastin recruitment to invadopodia, MMP‑9 activity and concomitant extracellular matrix degradation. Conclusion: Altogether, our results demonstrate that L‑plastin Ser5 phosphorylation increases breast cancer cell invasiveness. Being a downstream molecule of both ERK/MAPK and PI3K/SGK pathways, L‑plastin is proposed here as a potential target for therapeutic approaches that are aimed at blocking dysregulated signalling outcome of both pathways and, thus, at impairing cancer cell invasion and metastasis formation. [less ▲]

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See detailCausal dynamical modelling predicts novel regulatory genes of FOXP3 in human regulatory T cells
Sawlekar, Rucha UL; Magni, Stefano UL; Chapelle, Christophe et al

E-print/Working paper (2020)

Detailed reference viewed: 100 (5 UL)