title: TRAF3 deficiency promotes metabolic reprogramming in B cells.
abstract: The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species. Chemical inhibition of glucose metabolism or glucose deprivation substantially attenuated the enhanced survival of TRAF3-deficient B cells, with a decrease in the pro-survival protein Mcl-1. Changes in Glut1 and Mcl-1 levels, glucose uptake and B cell number in the absence of TRAF3 were all dependent upon NF-κB inducing kinase (NIK). These results indicate that TRAF3 deficiency suffices to metabolically reprogram B cells, a finding that improves our understanding of the role of TRAF3 as a tumor suppressor, and suggests potential therapeutic strategies.
authors.affiliation: Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.|Medical Scientist Training Program, The University of Iowa, Carver College of Medicine, 2206 MERF, Iowa City, IA 52242-2600, USA.|Immunology Graduate Program, 357 Medical Research Center, Iowa City, IA 52242-1182, USA.
authors.forename: Nurbek
authors.initials: N
authors.lastname: Mambetsariev
authors.affiliation: Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.|Immunology Graduate Program, 357 Medical Research Center, Iowa City, IA 52242-1182, USA.
authors.forename: Wai W
authors.initials: WW
authors.lastname: Lin
authors.affiliation: Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.|Immunology Graduate Program, 357 Medical Research Center, Iowa City, IA 52242-1182, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Wallis
authors.affiliation: Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.|Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Stunz
authors.affiliation: Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.|Medical Scientist Training Program, The University of Iowa, Carver College of Medicine, 2206 MERF, Iowa City, IA 52242-2600, USA.|Immunology Graduate Program, 357 Medical Research Center, Iowa City, IA 52242-1182, USA.|Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.|University of Iowa and DVA Medical Center, 601 Highway 6 West, Iowa City, IA 52246, USA.|Internal Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242, USA.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D065150:Cellular Reprogramming / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D005947:Glucose; D051272:Glucose Transporter Type 1; D006593:Hexokinase; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C579094:Mcl1 protein, mouse; C495678:Slc2a1 protein, mouse; C000598049:hexokinase 2, mouse