title: BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory.
abstract: Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived "memory" cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Sullivan
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lexus R
authors.initials: LR
authors.lastname: Johnson
authors.affiliation: Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Kang
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000071183:Autophagy-Related Proteins; D002478:Cells, Cultured; D006566:Herpesviridae Infections / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000821:virology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics*; D018146:Muromegalovirus / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; C508686:BNip3 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D017382:Reactive Oxygen Species; D044763:Ubiquitin-Conjugating Enzymes; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C568853:Atg3 protein, mouse