PhD, Institute For Stem Cell Science and Regenerative Medicine (Instem-DBT), Regulation of cell signalling (2022)
M.Sc, University of Delhi, Biochemistry (2013)
B.Sc, University of Delhi, Biochemistry (2011)
Rosa Bacchetta, Postdoctoral Faculty Sponsor
Notch1 Modulation of Cellular Calcium Regulates Mitochondrial Metabolism and Anti-Apoptotic Activity in T-Regulatory Cells.
Frontiers in immunology
2022; 13: 832159
As the major hub of metabolic activity and an organelle sequestering pro-apoptogenic intermediates, mitochondria lie at the crossroads of cellular decisions of death and survival. Intracellular calcium is a key regulator of these outcomes with rapid, uncontrolled uptake into mitochondria, activating pro-apoptotic cascades that trigger cell death. Here, we show that calcium uptake and mitochondrial metabolism in murine T-regulatory cells (Tregs) is tuned by Notch1 activity. Based on analysis of Tregs and the HEK cell line, we present evidence that modulation of cellular calcium dynamics underpins Notch1 regulation of mitochondrial homeostasis and consequently anti-apoptotic activity. Targeted siRNA-mediated ablations reveal dependency on molecules controlling calcium release from the endoplasmic reticulum (ER) and the chaperone, glucose-regulated protein 75 (Grp75), the associated protein Voltage Dependent Anion Channel (VDAC)1 and the Mitochondrial Calcium Uniporter (MCU), which together facilitate ER calcium transfer and uptake into the mitochondria. Endogenous Notch1 is detected in immune-complexes with Grp75 and VDAC1. Deficits in mitochondrial oxidative and survival in Notch1 deficient Tregs, were corrected by the expression of recombinant Notch1 intracellular domain, and in part by recombinant Grp75. Thus, the modulation of calcium dynamics and consequently mitochondrial metabolism underlies Treg survival in conditions of nutrient stress. This work positions a key role for Notch1 activity in these outcomes.
View details for DOI 10.3389/fimmu.2022.832159
View details for PubMedID 35222416
View details for PubMedCentralID PMC8866856
Sirtuin1 meditated modification of Notch1 intracellular domain regulates nucleolar localization and activation of distinct signaling cascades
Front Cell Dev Biol .
2022; 10: 988816
View details for DOI 10.3389/fcell.2022.988816
Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival
Life Science Alliance
2022; 5: 12
View details for DOI 10.26508/lsa.202201663
Spatial regulation and generation of diversity in signaling pathways.
Journal of biosciences
Signaling pathways orchestrate diverse cellular outcomes in the same tissue, spatially and temporally. These interactions, which are played out in micro-environments within cells and involve a relatively small number of core pathways, are the key to the development and function of multi-cellular organisms. How these outcomes are regulated has prompted interest in intracellular mechanisms that build diversity in signaling outcomes. This review specifically addresses spatial positioning of molecules as a means of enabling interactions and novel outcomes of signaling cascades. Using the Notch and Ras pathways as exemplars, we describe mechanisms that contribute to diverse signaling outcomes.
View details for PubMedID 33785678
Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors
Cell Death Discov.
2020; 6: 7
View details for DOI 10.1038/s41420-020-0242-y