title: The lysine deacetylase Sirtuin 1 modulates the localization and function of the Notch1 receptor in regulatory T cells.
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 Tregcell 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 Tregcells. 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 Tregcells. Loss of Sirt1 compromised Tregcell 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.
authors.affiliation: National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India.|Manipal University, Manipal, Karnataka, India.
authors.forename: Nimi
authors.identifier: http://orcid.org/0000-0001-5313-8183
authors.initials: N
authors.lastname: Marcel
authors.affiliation: National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India.
authors.forename: Lakshmi R
authors.identifier: http://orcid.org/0000-0002-8811-4795
authors.initials: LR
authors.lastname: Perumalsamy
authors.affiliation: National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India.|Manipal University, Manipal, Karnataka, India.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Shukla
authors.affiliation: National Centre for Biological Sciences, Bengaluru, Karnataka 560065, India. sarina@ncbs.res.in.|Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru, Karnataka 560065, India.
authors.forename: Apurva
authors.identifier: http://orcid.org/0000-0003-0851-4818
authors.initials: A
authors.lastname: Sarin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001120:Arginine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D051020:bcl-X Protein; D001120:Arginine; D056564:Sirtuin 1; D008239:Lysine