The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells.
Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.
Alves
Nuno L
NL
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
Derks
Ingrid A M
IAM
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
Berk
Erik
E
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
Spijker
René
R
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands; Department of Hematology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
van Lier
René A W
RAW
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands.
Eldering
Eric
E
Department of Experimental Immunology, Academic Medical Center, 1005 AZ Amsterdam, The Netherlands. Electronic address: e.eldering@amc.uva.nl.
D017209:Apoptosis / Q000235:genetics; D018106:CD28 Antigens / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018106:CD28 Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; D005947:Glucose