Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.
Animals
Anti-Bacterial Agents
/ therapeutic use
Autoimmunity
/ drug effects
Cell Differentiation
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
Humans
Linezolid
/ therapeutic use
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ genetics
Mitochondrial Proteins
/ genetics
Molecular Targeted Therapy
Multiple Sclerosis
/ drug therapy
NAD
/ metabolism
Oxidative Phosphorylation
Peptide Elongation Factor G
/ genetics
Peptides, Cyclic
/ therapeutic use
Ribosomes
/ metabolism
Th17 Cells
/ physiology
Argyrin
Linezolid
NAD+
T cells
antibiotics
autoimmunity
elongation factor G1
mitochondria
mitochondrial translation
ribosome-targeting
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
12 01 2021
12 01 2021
Historique:
received:
10
11
2019
revised:
16
09
2020
accepted:
03
11
2020
pubmed:
26
11
2020
medline:
10
9
2021
entrez:
25
11
2020
Statut:
ppublish
Résumé
While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.
Identifiants
pubmed: 33238133
pii: S1074-7613(20)30466-0
doi: 10.1016/j.immuni.2020.11.001
pmc: PMC7837214
mid: NIHMS1668683
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Mitochondrial Proteins
0
Peptide Elongation Factor G
0
Peptides, Cyclic
0
argyrin c
0
NAD
0U46U6E8UK
Linezolid
ISQ9I6J12J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
68-83.e6Subventions
Organisme : NIAID NIH HHS
ID : P01 AI056299
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA065493
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118979
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI034495
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155114
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL056067
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
Références
J Antibiot (Tokyo). 2002 Jun;55(6):543-51
pubmed: 12195959
Nature. 2013 May 23;497(7450):451-7
pubmed: 23698443
J Am Board Fam Med. 2008 Jul-Aug;21(4):261-8
pubmed: 18612052
Clin Infect Dis. 2009 Jan 15;48(2):203-12
pubmed: 19072714
Int J Mol Sci. 2017 Dec 08;18(12):
pubmed: 29292737
Cancer Cell. 2011 Nov 15;20(5):674-88
pubmed: 22094260
Genes Dev. 2018 Oct 1;32(19-20):1285-1296
pubmed: 30275044
Cold Spring Harb Perspect Biol. 2012 May 01;4(5):
pubmed: 22550233
Cell Metab. 2015 Sep 1;22(3):485-98
pubmed: 26299452
Nat Rev Microbiol. 2010 Jun;8(6):423-35
pubmed: 20440275
Genomics. 2001 May 15;74(1):109-14
pubmed: 11374907
Nature. 2019 Jul;571(7765):403-407
pubmed: 31217581
Semin Immunol. 2016 Oct;28(5):514-524
pubmed: 27825556
Cell Rep. 2019 Jul 2;28(1):159-171.e4
pubmed: 31269437
Cell. 2019 Sep 5;178(6):1313-1328.e13
pubmed: 31491384
PLoS Biol. 2013 Oct;11(10):e1001674
pubmed: 24115907
Diagn Microbiol Infect Dis. 2002 May;43(1):65-73
pubmed: 12052631
Science. 2016 Apr 29;352(6285):535-8
pubmed: 27126035
Hum Mol Genet. 2013 Mar 15;22(6):1132-9
pubmed: 23223015
Mol Cell. 2007 May 11;26(3):393-402
pubmed: 17499045
Med Clin (Barc). 2017 Oct 23;149(8):369
pubmed: 28571952
Cold Spring Harb Perspect Biol. 2010 May;2(5):a000414
pubmed: 20452953
Cell Metab. 2017 Jun 6;25(6):1254-1268.e7
pubmed: 28591633
FEBS Lett. 2005 Nov 21;579(28):6423-7
pubmed: 16271719
Lancet. 1963 Apr 13;1(7285):785-9
pubmed: 13990765
J Immunol. 2009 Nov 15;183(10):6041-50
pubmed: 19841183
Am J Cancer Res. 2017 Dec 01;7(12):2395-2405
pubmed: 29312795
Antimicrob Agents Chemother. 2004 Jan;48(1):281-4
pubmed: 14693551
Toxicol Appl Pharmacol. 2004 Apr 1;196(1):68-79
pubmed: 15050409
Blood. 2017 Feb 9;129(6):729-739
pubmed: 27879260
Nat Immunol. 2003 Apr;4(4):330-6
pubmed: 12612578
Cell Metab. 2016 Jul 12;24(1):104-17
pubmed: 27411012
Genome Biol. 2016 May 12;17:103
pubmed: 27176874
Mitochondrion. 2007 Dec;7(6):374-85
pubmed: 17890163
Int Immunol. 2001 Jul;13(7):921-31
pubmed: 11431422
J Immunol. 2000 Nov 1;165(9):5017-26
pubmed: 11046030
Immunity. 2013 Feb 21;38(2):225-36
pubmed: 23415911
Drugs. 2001;61(4):525-51
pubmed: 11324682
Nature. 2011 Jun 15;474(7351):337-42
pubmed: 21677750
BMC Med Genet. 2015 Feb 04;16:3
pubmed: 25650108
Allergy Asthma Clin Immunol. 2015 Jan 09;11(1):1
pubmed: 25784943
Oncotarget. 2015 Mar 10;6(7):4569-84
pubmed: 25625193
Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1539-1555
pubmed: 28215579
PLoS One. 2012;7(9):e42657
pubmed: 22970117
Prim Care Companion J Clin Psychiatry. 2009;11(6):353-6
pubmed: 20098528
Cell. 2016 Jun 30;166(1):63-76
pubmed: 27293185
PLoS One. 2014 May 07;9(5):e96566
pubmed: 24804722
Eur J Hum Genet. 2012 Jun;20(6):607-12
pubmed: 22317974
Cell. 2013 Jun 6;153(6):1239-51
pubmed: 23746840
Mol Cell. 2009 Aug 28;35(4):502-10
pubmed: 19716793
Biochem Soc Trans. 2003 Dec;31(Pt 6):1143-51
pubmed: 14641014
Eukaryot Cell. 2005 Dec;4(12):2078-86
pubmed: 16339725
Nat Methods. 2008 Jul;5(7):621-8
pubmed: 18516045
Redox Biol. 2017 Oct;13:244-254
pubmed: 28600981
J Clin Invest. 2014 Jul;124(7):2836-40
pubmed: 24983424
Am J Dig Dis. 1975 Apr;20(4):295-7
pubmed: 1130357
J Lab Clin Med. 1973 May;81(5):713-8
pubmed: 4698658
Eur J Immunol. 2011 Mar;41(3):833-44
pubmed: 21287545
Front Immunol. 2018 Mar 13;9:302
pubmed: 29593707
Sci Rep. 2018 Sep 21;8(1):14190
pubmed: 30242167
Eur J Biochem. 1999 May;262(1):108-16
pubmed: 10231371
Cell. 2016 Oct 6;167(2):471-483.e10
pubmed: 27693358
Naunyn Schmiedebergs Arch Pharmacol. 1975;290(2-3):161-73
pubmed: 171591
Medicine (Baltimore). 2018 Sep;97(36):e12114
pubmed: 30200095
Chem Biol Drug Des. 2014 Jul;84(1):99-107
pubmed: 24521156
J Exp Med. 2003 Dec 15;198(12):1875-86
pubmed: 14676299
Mayo Clin Proc. 1999 Apr;74(4):420-34
pubmed: 10221472
Front Immunol. 2019 Jun 14;10:1374
pubmed: 31258540
Cancer Lett. 2017 Jul 28;399:20-28
pubmed: 28408354
Cell. 2016 Jun 30;166(1):9-10
pubmed: 27368094
Cell Rep. 2015 Mar 17;10(10):1681-1691
pubmed: 25772356
Cell. 2015 Jul 30;162(3):552-63
pubmed: 26232225
Cancer Cell. 2008 Jul 8;14(1):23-35
pubmed: 18598941
Drug Saf. 2008;31(9):753-68
pubmed: 18707190
Pharmacogenomics. 2010 Sep;11(9):1185-7
pubmed: 20860455
Drug Des Devel Ther. 2018 Jun 18;12:1759-1767
pubmed: 29950810
J Biol Chem. 1998 Sep 4;273(36):22983-9
pubmed: 9722521
Cell Metab. 2020 Apr 7;31(4):809-821.e6
pubmed: 32187526
Antimicrob Agents Chemother. 2006 Jun;50(6):2042-9
pubmed: 16723564
Immunity. 2011 Dec 23;35(6):871-82
pubmed: 22195744
Protein Expr Purif. 2004 Oct;37(2):368-76
pubmed: 15358359
Science. 2020 Jun 19;368(6497):1371-1376
pubmed: 32439659