title: TNFR-associated factor 6 and TGF-β-activated kinase 1 control signals for a senescence response by an endosomal NK cell receptor.
abstract: The endosomal innate receptor CD158d (killer cell Ig-like receptor 2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist Ab). These senescent NK cells display a senescence-associated secretory phenotype, and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TNFR-associated factor 6 (TRAF6) binding motif, which was required for CD158d-induced NF-κB activation and IL-8 secretion, TRAF6 association with CD158d, and TRAF6 recruitment to CD158d(+) endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TGF-β-activated kinase 1 (TAK1) for NF-κB-dependent proinflammatory responses. Small interfering RNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TRAF6 association with CD158d, induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the senescence-associated secretory phenotype signature. Our results reveal that a prototypic TLR and TNFR signaling pathway is used by a killer cell Ig-like receptor that promotes secretion of proinflammatory and proangiogenic mediators as part of a unique senescence phenotype in NK cells.
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors: Sumati
authors: S
authors: Rajagopalan
authors: Elizabeth C
authors: EC
authors: Lee
authors: Matthew L
authors: ML
authors: DuPrie
authors: Eric O
authors: EO
authors: Long
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D054345:Receptors, KIR2DL4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D054345:Receptors, KIR2DL4; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7; C515079:KIR2DL4 protein, human