title: Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells.
abstract: In the HLA class II-associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.
authors.affiliation: Division of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujii
authors.forename: Shalini V
authors.initials: SV
authors.lastname: Mohan
authors.forename: Jorg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D025481:Phosphofructokinase-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D005947:Glucose
references.citation: Biofactors. 1999;10(1):1-14
references.pmid: 10475585
references.citation: J Immunol. 2009 Apr 1;182(7):4046-55
references.pmid: 19299702
references.citation: Nat Rev Immunol. 2012 Apr 20;12(5):325-38
references.pmid: 22517423
references.citation: Semin Immunol. 2012 Dec;24(6):414-20
references.pmid: 23332779
references.citation: Cancer Res. 2002 Oct 15;62(20):5881-7
references.pmid: 12384552
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9203-8
references.pmid: 10922071
references.citation: Nat Med. 2012 Oct;18(10):1518-24
references.pmid: 23023500
references.citation: J Immunol Methods. 2006 Mar 20;310(1-2):30-9
references.pmid: 16516225
references.citation: FEBS Lett. 1993 Oct 25;333(1-2):169-74
references.pmid: 8224160
references.citation: Cold Spring Harb Symp Quant Biol. 2011;76:211-6
references.pmid: 22096029
references.citation: Curr Opin Immunol. 2010 Jun;22(3):321-5
references.pmid: 20392618
references.citation: J Biochem. 1997 Apr;121(4):724-30
references.pmid: 9163524
references.citation: J Clin Invest. 2005 Nov;115(11):3083-92
references.pmid: 16239971
references.citation: Curr Opin Immunol. 2012 Aug;24(4):488-93
references.pmid: 22565047
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16677-82
references.pmid: 18946037
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):E1629-37
references.pmid: 22615393
references.citation: Nat Immunol. 2012 Oct;13(10):907-15
references.pmid: 22990888
references.citation: Cell Death Differ. 2012 Jan;19(1):144-52
references.pmid: 21660048
references.citation: IUBMB Life. 2012 May;64(5):362-9
references.pmid: 22431005
references.citation: EMBO Mol Med. 2010 Oct;2(10):415-27
references.pmid: 20878914
references.citation: Blood. 2010 Dec 2;116(23):4806-14
references.pmid: 20716775
references.citation: Nat Rev Rheumatol. 2010 May;6(5):290-5
references.pmid: 20234359
references.citation: Biochem J. 1980 Dec 15;192(3):897-901
references.pmid: 6453589
references.citation: Nat Rev Immunol. 2011 Feb;11(2):109-17
references.pmid: 21233853
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):738-41
references.pmid: 20080744
references.citation: Immunity. 2006 Jun;24(6):703-716
references.pmid: 16782027
references.citation: Nature. 1976 Jun 24;261(5562):702-5
references.pmid: 934318
references.citation: J Immunol. 2009 Dec 15;183(12):8258-67
references.pmid: 20007589
references.citation: Nat Immunol. 2013 May;14(5):428-36
references.pmid: 23598398
references.citation: Biochem J. 2012 Aug 15;446(1):1-7
references.pmid: 22835215
references.citation: Immunity. 2013 Feb 21;38(2):225-36
references.pmid: 23415911
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Nat Cell Biol. 2010 Sep;12(9):823-30
references.pmid: 20811354
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18868-73
references.pmid: 20921411
references.citation: J Immunol. 2005 Jun 15;174(12):7592-9
references.pmid: 15944259
references.citation: Biosci Biotechnol Biochem. 2000 Oct;64(10):2047-52
references.pmid: 11129574
references.citation: J Exp Med. 2009 Jun 8;206(6):1435-49
references.pmid: 19451263
references.citation: Immunol Rev. 2012 Sep;249(1):59-71
references.pmid: 22889215
references.citation: Arthritis Res Ther. 2009;11(5):249
references.pmid: 19835638
references.citation: J Biol Chem. 1994 Dec 16;269(50):31484-90
references.pmid: 7989314
references.citation: J Clin Invest. 2013 Mar;123(3):966-72
references.pmid: 23454759
references.citation: Rheum Dis Clin North Am. 2010 May;36(2):297-310
references.pmid: 20510235
references.citation: Trends Biochem Sci. 2001 Jan;26(1):30-5
references.pmid: 11165514
references.citation: J Clin Invest. 1996 May 1;97(9):2027-37
references.pmid: 8621791
references.citation: Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10
references.pmid: 16932686
references.citation: Immunity. 2002 Jun;16(6):769-77
references.pmid: 12121659
references.citation: Exp Mol Pathol. 2009 Jun;86(3):174-9
references.pmid: 19454274
references.citation: J Immunol. 2011 Mar 15;186(6):3299-303
references.pmid: 21317389
references.citation: J Immunol. 2011 Feb 1;186(3):1564-74
references.pmid: 21191072
references.citation: Immunol Rev. 2005 Apr;204:55-73
references.pmid: 15790350
references.citation: Arthritis Rheum. 1998 Oct;41(10):1845-50
references.pmid: 9778226
references.citation: Cell. 2004 Apr 16;117(2):265-77
references.pmid: 15084263
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4360-5
references.pmid: 19255426
references.citation: J Immunol. 2001 Oct 15;167(8):4710-8
references.pmid: 11591802
references.citation: Biochem J. 2004 Aug 1;381(Pt 3):561-79
references.pmid: 15170386
references.citation: Annu Rev Physiol. 2013;75:685-705
references.pmid: 23140366
references.citation: Clin Cancer Res. 2005 Aug 15;11(16):5784-92
references.pmid: 16115917
references.citation: Aging Dis. 2011 Dec;2(6):524-37
references.pmid: 22396899
references.citation: J Transl Med. 2012 May 16;10:95
references.pmid: 22591674
references.citation: Nature. 2013 Jan 17;493(7432):346-55
references.pmid: 23325217
references.citation: PLoS One. 2012;7(2):e31219
references.pmid: 22359576
references.citation: J Neurooncol. 2008 Feb;86(3):257-64
references.pmid: 17805487
references.citation: Nat Rev Immunol. 2005 Nov;5(11):844-52
references.pmid: 16239903
references.citation: Annu Rev Immunol. 2013;31:259-83
references.pmid: 23298210
references.citation: Arthritis Rheum. 1995 Jan;38(1):44-8
references.pmid: 7818570
references.citation: Nat Rev Rheumatol. 2009 Oct;5(10):583-8
references.pmid: 19798035
references.citation: J Biol Chem. 2009 Sep 4;284(36):24223-32
references.pmid: 19473963
references.citation: Best Pract Res Clin Rheumatol. 2007 Oct;21(5):871-83
references.pmid: 17870033
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: PLoS One. 2011;6(9):e24179
references.pmid: 21957443
references.citation: Cell Mol Life Sci. 2012 May;69(10):1615-23
references.pmid: 22466672
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3047-52
references.pmid: 10077634
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2503-18
references.pmid: 15325588
references.citation: Immunity. 2011 Dec 23;35(6):871-82
references.pmid: 22195744
references.citation: Curr Opin Immunol. 2010 Jun;22(3):314-20
references.pmid: 20189791
references.citation: Nat Immunol. 2009 May;10(5):461-70
references.pmid: 19381141
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: Front Immunol. 2012 Aug 07;3:247
references.pmid: 22891069