Research ArticleImmunology

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

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Science Signaling  04 Apr 2017:
Vol. 10, Issue 473, eaah4679
DOI: 10.1126/scisignal.aah4679

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Another Notch in the belt for Sirt1

Regulatory T (Treg) cells suppress effector T cell function to prevent autoimmunity. Cell-based therapies to treat autoimmune diseases are effective only if Treg cells survive and are functional after being transferred to patients. Marcel et al. investigated how Notch signaling protects Treg cells from apoptosis induced by cytokine withdrawal. The enzyme SIRT1 deacetylated NIC, the intracellular domain of the Notch receptor, which retained NIC in the cytosol where it promoted anti-apoptotic signaling. In mouse models of inflammation, deletion of Sirt1 or Notch1 decreased Treg cell survival and exacerbated inflammatory disease. Together, these data suggest that the Sirt1-Notch signaling axis may be targeted therapeutically to manipulate Treg cell survival.


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.

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