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Sci Signal. 2017 Apr 4;10(473). pii: eaah4679. doi: 10.1126/scisignal.aah4679.

The lysine deacetylase Sirtuin 1 modulates the localization and function of the Notch1 receptor in regulatory T cells.

Author information

1
National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India.
2
Manipal University, Manipal, Karnataka, India.
3
National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India. sarina@ncbs.res.in.
4
Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru, Karnataka 560065, India.

Abstract

The ability to tune cellular functions in response to nutrient availability has important consequences for immune homeostasis. The activity of the receptor Notch in regulatory T (Treg) cells, which suppress the functions of effector T cells, is indispensable for Treg cell survival under conditions of diminished nutrient supply. Anti-apoptotic signaling induced by the Notch1 intracellular domain (NIC) originates from the cytoplasm and is spatially decoupled from the nuclear, largely transcriptional functions of NIC. We showed that Sirtuin 1 (Sirt1), which is an NAD+ (nicotinamide adenine dinucleotide)-dependent lysine deacetylase that inhibits NIC-dependent gene transcription, stabilized NIC proximal to the plasma membrane to promote the survival and function of activated Treg cells. Sirt1 was required for NIC-dependent protection from apoptosis in cell lines but not for the activity of the anti-apoptotic protein Bcl-xL. In addition, a variant NIC protein in which four lysines were mutated to arginines (NIC4KR) retained anti-apoptotic activity, but was not regulated by Sirt1, and reconstituted the functions of nonnuclear NIC in Notch1-deficient Treg cells. Loss of Sirt1 compromised Treg cell survival, resulting in antigen-induced T cell proliferation and inflammation in two mouse models. Thus, the Sirt1-Notch interaction may constitute an important checkpoint that tunes noncanonical Notch1 signaling.

PMID:
28377411
DOI:
10.1126/scisignal.aah4679
[Indexed for MEDLINE]

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