p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

Journal of Cell Biology - Tập 201 Số 4 - Trang 613-629 - 2013
Albert R. Davalos1,2, Misako Kawahara2, Gautam Malhotra2, Nicholas Schaum1, Jiahao Huang2, Urvi Ved2, Christian Beauséjour3, Jean‐Philippe Coppé2, Françis Rodier1,2, Judith Campisi1,2
1Buck Institute for Research on Aging, Novato, CA 94945 2
2Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720 1
3Département de Pharmacologie, CHU Ste-Justine, Montréal, QC H3T 1C5, Canada 3

Tóm tắt

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

Từ khóa


Tài liệu tham khảo

Acosta, 2008, Chemokine signaling via the CXCR2 receptor reinforces senescence, Cell., 133, 1006, 10.1016/j.cell.2008.03.038

Ammit, 2000, Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate, Am. J. Respir. Cell Mol. Biol., 23, 794, 10.1165/ajrcmb.23.6.4184

Andersson, 2011, HMGB1 is a therapeutic target for sterile inflammation and infection, Annu. Rev. Immunol., 29, 139, 10.1146/annurev-immunol-030409-101323

Andersson, 2002, HMGB1 as a DNA-binding cytokine, J. Leukoc. Biol., 72, 1084, 10.1189/jlb.72.6.1084

Banerjee, 2003, The acidic C-terminal domain and A-box of HMGB-1 regulates p53-mediated transcription, Nucleic Acids Res., 31, 3236, 10.1093/nar/gkg412

Bavik, 2006, The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms, Cancer Res., 66, 794, 10.1158/0008-5472.CAN-05-1716

Beauséjour, 2003, Reversal of human cellular senescence: roles of the p53 and p16 pathways, EMBO J., 22, 4212, 10.1093/emboj/cdg417

Bhaumik, 2009, MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8, Aging (Albany NY)., 1, 402, 10.18632/aging.100042

Bianchi, 2007, DAMPs, PAMPs and alarmins: all we need to know about danger, J. Leukoc. Biol., 81, 1, 10.1189/jlb.0306164

Bianchi, 2009, HMGB1 loves company, J. Leukoc. Biol., 86, 573, 10.1189/jlb.1008585

Bonaldi, 2003, Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion, EMBO J., 22, 5551, 10.1093/emboj/cdg516

Brezniceanu, 2003, HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma, FASEB J., 17, 1295, 10.1096/fj.02-0621fje

Campeau, 2009, A versatile viral system for expression and depletion of proteins in mammalian cells, PLoS ONE., 4, e6529, 10.1371/journal.pone.0006529

Campisi, 2001, Cellular senescence as a tumor-suppressor mechanism, Trends Cell Biol., 11, S27, 10.1016/S0962-8924(01)82148-6

Campisi, 2003, Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes, Exp. Gerontol., 38, 5, 10.1016/S0531-5565(02)00152-3

Campisi, 2007, Cellular senescence: when bad things happen to good cells, Nat. Rev. Mol. Cell Biol., 8, 729, 10.1038/nrm2233

Coppé, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol., 6, 2853, 10.1371/journal.pbio.0060301

Coppé, 2010, The senescence-associated secretory phenotype: the dark side of tumor suppression, Annu. Rev. Pathol., 5, 99, 10.1146/annurev-pathol-121808-102144

Coppé, 2010, A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen, PLoS ONE., 5, e9188, 10.1371/journal.pone.0009188

Coppé, 2011, Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype, J. Biol. Chem., 286, 36396, 10.1074/jbc.M111.257071

Coussens, 2002, Inflammation and cancer, Nature., 420, 860, 10.1038/nature01322

Davalos, 2003, Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks, J. Cell Biol., 162, 1197, 10.1083/jcb.200304016

Dimri, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc. Natl. Acad. Sci. USA., 92, 9363, 10.1073/pnas.92.20.9363

Dumitriu, 2005, HMGB1: guiding immunity from within, Trends Immunol., 26, 381, 10.1016/j.it.2005.04.009

Ellerman, 2007, Masquerader: high mobility group box-1 and cancer, Clin. Cancer Res., 13, 2836, 10.1158/1078-0432.CCR-06-1953

Falciola, 1997, High mobility group 1 protein is not stably associated with the chromosomes of somatic cells, J. Cell Biol., 137, 19, 10.1083/jcb.137.1.19

Franceschi, 2007, Inflammaging as a major characteristic of old people: can it be prevented or cured?, Nutr. Rev., 65, 173, 10.1301/nr.2007.dec.S173-S176

Freund, 2010, Inflammatory networks during cellular senescence: causes and consequences, Trends Mol. Med., 16, 238, 10.1016/j.molmed.2010.03.003

Freund, 2011, p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype, EMBO J., 30, 1536, 10.1038/emboj.2011.69

Gardella, 2002, The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway, EMBO Rep., 3, 995, 10.1093/embo-reports/kvf198

Goodwin, 1973, A new group of chromatin-associated proteins with a high content of acidic and basic amino acids, Eur. J. Biochem., 38, 14, 10.1111/j.1432-1033.1973.tb03026.x

Green, 2005, Apoptotic pathways: ten minutes to dead, Cell., 121, 671, 10.1016/j.cell.2005.05.019

Grosschedl, 1994, HMG domain proteins: architectural elements in the assembly of nucleoprotein structures, Trends Genet., 10, 94, 10.1016/0168-9525(94)90232-1

Gudkov, 1993, Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA, Proc. Natl. Acad. Sci. USA., 90, 3231, 10.1073/pnas.90.8.3231

Hayflick, 1965, The limited in vitro lifetime of human diploid cell strains, Exp. Cell Res., 37, 614, 10.1016/0014-4827(65)90211-9

Herbig, 2006, Cellular senescence in aging primates, Science., 311, 1257, 10.1126/science.1122446

Ivanov, 2007, A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA, Blood., 110, 1970, 10.1182/blood-2006-09-044776

Jayaraman, 1998, High mobility group protein-1 (HMG-1) is a unique activator of p53, Genes Dev., 12, 462, 10.1101/gad.12.4.462

Kawamoto, 2008, TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain, Eur. J. Pharmacol., 584, 40, 10.1016/j.ejphar.2008.01.026

Kim, 2009, Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling, Stem Cells., 27, 1987, 10.1002/stem.125

Klune, 2008, HMGB1: endogenous danger signaling, Mol. Med., 14, 476, 10.2119/2008-00034.Klune

Kohno, 2009, Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling, Cardiovasc. Res., 81, 565, 10.1093/cvr/cvn291

Kortlever, 2006, Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence, Nat. Cell Biol., 8, 877, 10.1038/ncb1448

Kosar, 2011, Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a), Cell Cycle., 10, 457, 10.4161/cc.10.3.14707

Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell., 134, 657, 10.1016/j.cell.2008.06.049

Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell., 133, 1019, 10.1016/j.cell.2008.03.039

Le, 2010, Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status, Aging Cell., 9, 398, 10.1111/j.1474-9726.2010.00567.x

Liu, 2006, HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers, Am. J. Physiol. Cell Physiol., 290, C990, 10.1152/ajpcell.00308.2005

Lotze, 2005, High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal, Nat. Rev. Immunol., 5, 331, 10.1038/nri1594

Lotze, 2007, The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity, Immunol. Rev., 220, 60, 10.1111/j.1600-065X.2007.00579.x

Müller, 2004, Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function, J. Intern. Med., 255, 332, 10.1111/j.1365-2796.2003.01296.x

Nair, 2005, Inhibition of p53 by lentiviral mediated shRNA abrogates G1 arrest and apoptosis in retinal pigmented epithelial cell line, Cell Cycle., 4, 697, 10.4161/cc.4.5.1672

Narita, 2003, Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence, Cell., 113, 703, 10.1016/S0092-8674(03)00401-X

Narita, 2006, A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation, Cell., 126, 503, 10.1016/j.cell.2006.05.052

Orjalo, 2009, Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network, Proc. Natl. Acad. Sci. USA., 106, 17031, 10.1073/pnas.0905299106

Ossovskaya, 1996, Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains, Proc. Natl. Acad. Sci. USA., 93, 10309, 10.1073/pnas.93.19.10309

Palumbo, 2007, Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation, J. Cell Biol., 179, 33, 10.1083/jcb.200704015

Park, 2003, Activation of gene expression in human neutrophils by high mobility group box 1 protein, Am. J. Physiol. Cell Physiol., 284, C870, 10.1152/ajpcell.00322.2002

Park, 2006, High mobility group box 1 protein interacts with multiple Toll-like receptors, Am. J. Physiol. Cell Physiol., 290, C917, 10.1152/ajpcell.00401.2005

Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol., 5, 741, 10.1038/ncb1024

Parrinello, 2005, Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation, J. Cell Sci., 118, 485, 10.1242/jcs.01635

Prieur, 2008, Cellular senescence in vivo: a barrier to tumorigenesis, Curr. Opin. Cell Biol., 20, 150, 10.1016/j.ceb.2008.01.007

Raucci, 2007, HMGB1: a signal of necrosis, Autoimmunity., 40, 285, 10.1080/08916930701356978

Rodier, 2011, Four faces of cellular senescence, J. Cell Biol., 192, 547, 10.1083/jcb.201009094

Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol., 11, 973, 10.1038/ncb1909

Rodier, 2011, DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion, J. Cell Sci., 124, 68, 10.1242/jcs.071340

Scaffidi, 2002, Release of chromatin protein HMGB1 by necrotic cells triggers inflammation, Nature., 418, 191, 10.1038/nature00858

Schiraldi, 2012, HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4, J. Exp. Med., 209, 551, 10.1084/jem.20111739

Semino, 2005, NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1, Blood., 106, 609, 10.1182/blood-2004-10-3906

Sha, 2008, HMGB1 develops enhanced proinflammatory activity by binding to cytokines, J. Immunol., 180, 2531, 10.4049/jimmunol.180.4.2531

Smart, 1999, Effects on normal fibroblasts and neuroblastoma cells of the activation of the p53 response by the nuclear export inhibitor leptomycin B, Oncogene., 18, 7378, 10.1038/sj.onc.1203260

Suzuki, 2008, Stress-induced premature senescence (SIPS)—influence of SIPS on radiotherapy, J. Radiat. Res. (Tokyo)., 49, 105, 10.1269/jrr.07081

Tang, 2010, High-mobility group box 1 and cancer, Biochim. Biophys. Acta., 1799, 131, 10.1016/j.bbagrm.2009.11.014

Tian, 2007, Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE, Nat. Immunol., 8, 487, 10.1038/ni1457

Venereau, 2012, Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release, J. Exp. Med., 209, 1519, 10.1084/jem.20120189

Wajapeyee, 2008, Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7, Cell., 132, 363, 10.1016/j.cell.2007.12.032

Wang, 2009, DNA damage response and cellular senescence in tissues of aging mice, Aging Cell., 8, 311, 10.1111/j.1474-9726.2009.00481.x

Wang, 1999, HMG-1 as a late mediator of endotoxin lethality in mice, Science., 285, 248, 10.1126/science.285.5425.248

Wang, 1999, Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes, Surgery., 126, 389, 10.1016/S0039-6060(99)70182-0

Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature., 445, 656, 10.1038/nature05529

Yamada, 2007, HMGB1, a novel inflammatory cytokine, Clin. Chim. Acta., 375, 36, 10.1016/j.cca.2006.07.019

Yang, 2012, Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1), Mol. Med., 18, 250, 10.2119/molmed.2011.00389