Notch1 regulated autophagy controls survival and suppressor activity of activated murine T-regulatory cells.
Cell survival is one of several processes regulated by the Notch pathway in mammalian cells. Here we report functional outcomes of non-nuclear Notch signaling to activate autophagy, a conserved cellular response to nutrient stress, regulating survival in murine natural T-regulatory cells (Tregs), an immune subset controlling tolerance and inflammation. Induction of autophagy required ligand-dependent, Notch intracellular domain (NIC) activity, which controlled mitochondrial organization and survival of activated Tregs. Consistently, NIC immune-precipitated Beclin and Atg14, constituents of the autophagy initiation complex. Further, ectopic expression of an effector of autophagy (Atg3) or recombinant NIC tagged to a nuclear export signal (NIC-NES), restored autophagy and suppressor function in Notch1(-/-) Tregs. Furthermore, Notch1 deficiency in the Treg lineage resulted in immune hyperactivity, implicating Notch activity in Treg homeostasis. Notch1 integration with autophagy, revealed in these experiments, holds implications for Notch regulated cell-fate decisions governing differentiation.
National Centre for Biological Sciences, Bengaluru, India.|Department of Biology, Manipal University, Manipal, India.
Nimi
N
Marcel
National Centre for Biological Sciences, Bengaluru, India.|Institute for Stem Cell Biology & Regenerative Medicine, Bengaluru, India.
Apurva
0000-0003-0851-4818
A
Sarin
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D002470:Cell Survival; D047468:Immunoprecipitation; D051379:Mice; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000378:metabolism
C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D033921:Vesicular Transport Proteins
Notch; Signaling; T-cells; apoptosis; autophagy; cell biology; immunology; mouse