title: A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.
abstract: Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.|Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lanna
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.|Núcleo de Doenças Infecciosas/Núcleo de Biotecnologia, Universidade Federal do Espírito Santo - UFES, Vitória, Brazil.
authors.forename: Daniel C O
authors.initials: DC
authors.lastname: Gomes
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Bojana
authors.identifier: 0000-0002-9672-3750
authors.initials: B
authors.lastname: Muller-Durovic
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonnell
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.|Navarrabiomed-Biomedical Research Centre, Fundación Miguel Servet, IdisNA, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Escors
authors.affiliation: Division of Medicine, University College London, London, London, UK.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Gilroy
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jun Hee
authors.identifier: 0000-0002-2200-6011
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007109:Immunity / Q000235:genetics; D000068884:Immunosenescence / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D055815:Young Adult; D000084622:Sestrins
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D006360:Heat-Shock Proteins; D048670:MAP Kinase Kinase 4; D034741:RNA, Small Interfering; C117338:SESN1 protein, human; D000084622:Sestrins