The NF-κB signaling system and the autophagic degradation pathway are crucial cellular survival mechanisms, both being well conserved during evolution. Emerging studies have indicated that the IKK/NF-κB signaling axis regulates autophagy in a context-dependent manner. IKK complex and NF-κB can enhance the expression of Beclin 1 and other autophagy-related proteins and stimulate autophagy whereas as a feedback response, autophagy can degrade IKK components. Moreover, NF-κB signaling activates the expression of autophagy inhibitors (e.g., A20 and Bcl-2/xL) and represses the activators of autophagy (BNIP3, JNK1, and ROS). Several studies have indicated that NF-κB signaling is enhanced both during aging and cellular senescence, inducing a proinflammatory phenotype. The aging process is also associated with a decline in autophagic degradation. It seems that the activity of Beclin 1 initiation complex could be impaired with aging, since the expression of Beclin 1 decreases as does the activity of type III PI3K. On the other hand, the expression of inhibitory Bcl-2/xL proteins increases with aging. We will review the recent literature on the control mechanisms of autophagy through IKK/NF-κB signaling and emphasize that NF-κB signaling could be a potent repressor of autophagy with ageing. 1. Introduction One part of the aging process involves a decline in cellular housekeeping functions disturbing the maintenance of organism homeostasis [1, 2]. The accumulation of damaged and defective components increases cellular stress, for example, oxidative stress, which activates cellular defence mechanisms including NF-κB signaling pathway and innate immunity system, such as inflammasomes [3–5] (Section 3.1). Aging is associated with a low-grade proinflammatory phenotype which further interferes with housekeeping and cellular homeostasis. Recent studies have indicated that autophagy is a crucial cleansing system preventing inflammation but its capacity clearly declines with aging [6–8]. The NF-κB signaling system and the autophagic degradation pathway have been closely conserved during evolution and emerging studies indicate that these systems have many context-dependent interactions with each other. We will review the recent literature on the control mechanisms of autophagy by NF-κB signaling and particularly we will focus on its context-dependent regulation during the aging process. 1.1. Autophagy By definition, autophagy or autophagocytosis is a cellular self-digestion process involving the uptake of cellular components and organelles for degradation by lysosomal
References
[1]
M. C. Haigis and B. A. Yankner, “The aging stress response,” Molecular Cell, vol. 40, no. 2, pp. 333–344, 2010.
[2]
H. Koga, S. Kaushik, and A. M. Cuervo, “Protein homeostasis and aging: the importance of exquisite quality control,” Ageing Research Reviews, vol. 10, no. 2, pp. 205–215, 2011.
[3]
T. Finkel and N. J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, vol. 408, no. 6809, pp. 239–247, 2000.
[4]
O. Gross, C. J. Thomas, G. Guarda, and J. Tschopp, “The inflammasome: an integrated view,” Immunological Reviews, vol. 243, no. 1, pp. 136–151, 2011.
[5]
A. Salminen, K. Kaarniranta, and A. Kauppinen, “Inflammaging: disturbed interplay between autophagy and inflammasomes,” Aging (Albany NY), vol. 4, no. 3, pp. 1–10, 2012.
[6]
A. M. Cuervo, “Autophagy and aging: keeping that old broom working,” Trends in Genetics, vol. 24, no. 12, pp. 604–612, 2008.
[7]
A. Salminen and K. Kaarniranta, “Regulation of the aging process by autophagy,” Trends in Molecular Medicine, vol. 15, no. 5, pp. 217–224, 2009.
[8]
Y. S. Rajawat, Z. Hilioti, and I. Bossis, “Aging: central role for autophagy and the lysosomal degradative system,” Ageing Research Reviews, vol. 8, no. 3, pp. 199–213, 2009.
[9]
D. J. Klionsky, “Autophagy: from phenomenology to molecular understanding in less than a decade,” Nature Reviews Molecular Cell Biology, vol. 8, no. 11, pp. 931–937, 2007.
[10]
N. Mizushima, T. Yoshimori, and Y. Ohsumi, “The role of Atg proteins in autophagosome formation,” Annual Reviews in Cell and Developmental Biology, vol. 27, no. 1, pp. 107–132, 2011.
[11]
I. Tanida, “Autophagosome formation and molecular mechanism of autophagy,” Antioxidants and Redox Signaling, vol. 14, no. 11, pp. 2201–2214, 2011.
[12]
S. F. Funderburk, Q. J. Wang, and Z. Yue, “The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond,” Trends in Cell Biology, vol. 20, no. 6, pp. 355–362, 2010.
[13]
C. He and B. Levine, “The Beclin 1 interactome,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 140–149, 2010.
[14]
K. Matsunaga, E. Morita, T. Saitoh et al., “Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L,” Journal of Cell Biology, vol. 190, no. 4, pp. 511–521, 2010.
[15]
S. Sinha and B. Levine, “The autophagy effector Beclin 1: a novel BH3-only protein,” Oncogene, vol. 27, no. 1, supplement, pp. S137–S148, 2008.
[16]
Y. Wei, S. Pattingre, S. Sinha, M. Bassik, and B. Levine, “JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy,” Molecular Cell, vol. 30, no. 6, pp. 678–688, 2008.
[17]
G. Bellot, R. Garcia-Medina, P. Gounon et al., “Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2570–2581, 2009.
[18]
R. Kang, H. J. Zeh, M. T. Lotze, and D. Tang, “The Beclin 1 network regulates autophagy and apoptosis,” Cell Death and Differentiation, vol. 18, no. 4, pp. 571–580, 2011.
[19]
C. He and D. J. Klionsky, “Regulation mechanisms and signaling pathways of autophagy,” Annual Review of Genetics, vol. 43, pp. 67–93, 2009.
[20]
G. Kroemer, G. Mari？o, and B. Levine, “Autophagy and the Integrated Stress Response,” Molecular Cell, vol. 40, no. 2, pp. 280–293, 2010.
[21]
B. Ravikumar, S. Sarkar, J. E. Davies et al., “Regulation of mammalian autophagy in physiology and pathophysiology,” Physiological Reviews, vol. 90, no. 4, pp. 1383–1435, 2010.
[22]
B. Caballero and A. Coto-Montes, “An insight into the role of autophagy in cell responses in the aging and neurodegenerative brain,” Histology and Histopathology, vol. 27, no. 3, pp. 263–275, 2012.
[23]
A. Oeckinghaus and S. Ghosh, “The NF-kappaB family of transcription factors and its regulation,” Cold Spring Harbor Perspectives in Biology, vol. 1, no. 4, article a000034, 2009.
[24]
G. Ghosh, V. Y. Wang, D. B. Huang, and A. Fusco, “NF-κB regulation: lessons from structures,” Immunological Reviews, vol. 246, no. 1, pp. 36–58, 2012.
[25]
M. Hinz, S. C. Arslan, and C. Scheidereit, “It takes two to tango: IκBs, the multifunctional partners of NF-κB,” Immunological Reviews, vol. 246, no. 1, pp. 59–76, 2012.
[26]
P. Tieri, A. Termanini, E. Bellavista, S. Salvioli, M. Capri, and C. Franceschi, “Charting the NF-κB pathway interactome map,” PLoS ONE, vol. 7, no. 3, Article ID e32678, 2012.
[27]
N. D. Perkins, “Integrating cell-signalling pathways with NF-κB and IKK function,” Nature Reviews Molecular Cell Biology, vol. 8, no. 1, pp. 49–62, 2007.
[28]
M. S. Hayden and S. Ghosh, “Shared Principles in NF-κB Signaling,” Cell, vol. 132, no. 3, pp. 344–362, 2008.
[29]
A. Oeckinghaus, M. S. Hayden, and S. Ghosh, “Crosstalk in NF-κB signaling pathways,” Nature Immunology, vol. 12, no. 8, pp. 695–708, 2011.
[30]
A. Chariot, “The NF-κB-independent functions of IKK subunits in immunity and cancer,” Trends in Cell Biology, vol. 19, no. 8, pp. 404–413, 2009.
[31]
B. Huang, X. D. Yang, A. Lamb, and L. F. Chen, “Posttranslational modifications of NF-κB: another layer of regulation for NF-κB signaling pathway,” Cellular Signalling, vol. 22, no. 9, pp. 1282–1290, 2010.
[32]
S. T. Smale, “Hierarchies of NF-κB target-gene regulation,” Nature Immunology, vol. 12, no. 8, pp. 689–694, 2011.
[33]
N. ] Sen, B. D. Paul, M. M. Gadalla et al., “Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions,” Molecular Cell, vol. 45, no. 1, pp. 13–24, 2012.
[34]
T. Lawrence and C. Fong, “The resolution of inflammation: anti-inflammatory roles for NF-κB,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 4, pp. 519–523, 2010.
[35]
Q. Meng and D. Cai, “Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase β (IKKβ)/NF-κB pathway,” The Journal of Biological Chemistry, vol. 286, no. 37, pp. 32324–32332, 2011.
[36]
B. Levine, N. Mizushima, and H. W. Virgin, “Autophagy in immunity and inflammation,” Nature, vol. 469, no. 7330, pp. 323–335, 2011.
[37]
A. Salminen, J. M. T. Hyttinen, and K. Kaarniranta, “AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan,” Journal of Molecular Medicine, vol. 89, no. 7, pp. 667–676, 2011.
[38]
F. Yeung, J. E. Hoberg, C. S. Ramsey et al., “Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase,” EMBO Journal, vol. 23, no. 12, pp. 2369–2380, 2004.
[39]
I. H. Lee , L. Cao, R. Mostoslavsky et al., “A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 9, pp. 3374–3379, 2008.
[40]
A. Trocoli and M. Djavaheri-Mergny, “The complex interplay between autophagy and NF-κB signaling pathways in cancer cells,” American Journal of Cancer Research, vol. 1, no. 5, pp. 629–649, 2011.
[41]
A. Criollo, L. Senovilla, H. Authier et al., “The IKK complex contributes to the induction of autophagy,” EMBO Journal, vol. 29, no. 3, pp. 619–631, 2010.
[42]
W. C. Comb, P. Cogswell, R. Sitcheran, and A. S. Baldwin, “IKK-dependent, NF-κB-independent control of autophagic gene expression,” Oncogene, vol. 30, no. 14, pp. 1727–1732, 2011.
[43]
W. C. Comb, J. E. Hutti, P. Cogswell, L. C. Cantley, and A. S. Baldwin, “p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation,” Molecular Cell, vol. 45, no. 6, pp. 719–730, 2012.
[44]
M. Broemer, D. Krappmann, and C. Scheidereit, “Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation,” Oncogene, vol. 23, no. 31, pp. 5378–5386, 2004.
[45]
M. Hinz, M. Broemer, S. ？. Arslan et al., “Signal responsiveness of IκB kinases is determined by Cdc37-assisted transient interaction with Hsp90,” The Journal of Biological Chemistry, vol. 282, no. 44, pp. 32311–32319, 2007.
[46]
A. Salminen, T. Paimela, T. Suuronen, and K. Kaarniranta, “Innate immunity meets with cellular stress at the IKK complex: regulation of the IKK complex by HSP70 and HSP90,” Immunology Letters, vol. 117, no. 1, pp. 9–15, 2008.
[47]
J. F. Pittet, H. Lee, M. Pespeni, A. O'Mahony, J. Roux, and W. J. Welch, “Stress-induced inhibition of the NF-κB signaling pathway results from the insolubilization of the IκB kinase complex following its dissociation from heat shock protein 90,” Journal of Immunology, vol. 174, no. 1, pp. 384–394, 2005.
[48]
G. Qing, P. Yan, and G. Xiao, “Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IκB kinase (IKK),” Cell Research, vol. 16, no. 11, pp. 895–901, 2006.
[49]
G. Qing, P. Yan, Z. Qu, H. Liu, and G. Xiao, “Hsp90 regulates processing of NF-kB2 p100 involving protection of NF-kB-inducing kinase (NIK) from autophagy-mediated degradation,” Cell Research, vol. 17, no. 6, pp. 520–530, 2007.
[50]
M. Niida, M. Tanaka, and T. Kamitani, “Downregulation of active IKKβ by Ro52-mediated autophagy,” Molecular Immunology, vol. 47, no. 14, pp. 2378–2387, 2010.
[51]
J. E. Kim, D. J. You, C. Lee, C. Ahn, J. Y. Seong, and J. I. Hwang, “Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation,” Cellular Signalling, vol. 22, no. 11, pp. 1645–1654, 2010.
[52]
M. Nivon, E. Richet, P. Codogno, A. P. Arrigo, and C. Kretz-Remy, “Autophagy activation by NFκB is essential for cell survival after heat shock,” Autophagy, vol. 5, no. 6, pp. 766–783, 2009.
[53]
M. Nivon, M. Abou-Samra, E. Richet, B. Guyot, A. P. Arrigo, and C. Kretz-Remy, “NF-κB regulates protein quality control after heat stress through modulation of the BAG3-HspB8,” Journal of Cell Science, vol. 125, no. 1, pp. 1–11, 2012.
[54]
S. Carra, S. J. Seguin, and J. Landry, “HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy,” Autophagy, vol. 4, no. 2, pp. 237–239, 2008.
[55]
C. Kretz-Remy, B. Munseh, and A. P. Arrigo, “NFκB-dependent transcriptional activation during heat shock recovery: thermolability of the NF-κB·IκB complex,” The Journal of Biological Chemistry, vol. 276, no. 47, pp. 43723–43733, 2001.
[56]
T. Copetti, C. Bertoli, E. Dalla, F. Demarchi, and C. Schneider, “p65/RelA modulates BECN1 transcription and autophagy,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2594–2608, 2009.
[57]
S. Bhatnagar, A. Mittal, S. K. Gupta, and A. Kumar, “TWEAK causes myotubes atrophy through coordinated activation of ubiquitin-proteasome system, autophagy, and caspases,” Journal of Cellular Physiology, vol. 227, no. 3, pp. 1042–1051, 2012.
[58]
C. Dogra, H. Changotra, N. Wedhas, X. Qin, J. E. Wergedal, and A. Kumar, “TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine,” FASEB Journal, vol. 21, no. 8, pp. 1857–1869, 2007.
[59]
A. Kumar, S. Bhatnagar, and P. K. Paul, “TWEAK and TRAF6 regulate skeletal muscle atrophy,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 15, no. 2, pp. 233–239, 2012.
[60]
C. S. Shi and J. H. Kehrl, “TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced Autophagy,” Science Signaling, vol. 3, no. 123, article ra42, 2010.
[61]
Q. Jiang, Y. Wang, T. Li et al., “Heat shock protein 90-mediated inactivation of nuclear factor-kB switches autophagy to apoptosis through becn1 transcriptional inhibition in selenite-induced NB4 cells,” Molecular Biology of the Cell, vol. 22, no. 8, pp. 1167–1180, 2011.
[62]
S. Romano, A. D'Angelillo, R. Pacelli et al., “Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells,” Cell Death and Differentiation, vol. 17, no. 1, pp. 145–157, 2010.
[63]
Y. Tsuboi, M. Kurimoto, S. Nagai et al., “Induction of autophagic cell death and radiosensitization by the pharmacological inhibition of nuclear factor-kappa B activation in human glioma cell lines: laboratory investigation,” Journal of Neurosurgery, vol. 110, no. 3, pp. 594–604, 2009.
[64]
Y. Zhang, Y. Wu, D. Wu, S. I. Tashiro, S. Onodera, and T. Ikejima, “NF-κb facilitates oridonin-induced apoptosis and autophagy in HT1080 cells through a p53-mediated pathway,” Archives of Biochemistry and Biophysics, vol. 489, no. 1-2, pp. 25–33, 2009.
[65]
J. Hwang, H. J. Lee, W. H. Lee, and K. Suk, “NF-B as a common signaling pathway in ganglioside-induced autophagic cell death and activation of astrocytes,” Journal of Neuroimmunology, vol. 226, no. 1-2, pp. 66–72, 2010.
[66]
G. Kroemer and B. Levine, “Autophagic cell death: the story of a misnomer,” Nature Reviews Molecular Cell Biology, vol. 9, no. 12, pp. 1004–1010, 2008.
[67]
M. Djavaheri-Mergny, M. Amelotti, J. Mathieu et al., “NF-κB activation represses tumor necrosis factor-α-induced autophagy,” The Journal of Biological Chemistry, vol. 281, no. 41, pp. 30373–30382, 2006.
[68]
J. Huang, G. Y. Lam, and J. H. Brumell, “Autophagy signaling through reactive oxygen species,” Antioxidants and Redox Signaling, vol. 14, no. 11, pp. 2215–2231, 2011.
[69]
D. F. Lee, H. P. Kuo, C. T. Chen et al., “IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway,” Cell, vol. 130, no. 3, pp. 440–455, 2007.
[70]
H. C. Dan and A. S. Baldwin, “Differential involvement of IκB kinases α and β in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt,” Journal of Immunology, vol. 180, no. 11, pp. 7582–7589, 2008.
[71]
S. Kim, C. Domon-Dell, J. Kang, D. H. Chung, J. N. Freund, and B. M. Evers, “Down-regulation of the tumor Ssuppressor PTEN by the tumor necrosis factor-α/nuclear factor-κB (NF-κB)-inducing kinase/NF-κB pathway is linked to a default IκB-α Autoregulatory Loop,” The Journal of Biological Chemistry, vol. 279, no. 6, pp. 4285–4291, 2004.
[72]
K. M. Vasudevan, S. Gurumurthy, and V. M. Rangnekar, “Suppression of PTEN Expression by NF-κB Prevents Apoptosis,” Molecular and Cellular Biology, vol. 24, no. 3, pp. 1007–1021, 2004.
[73]
A. Salminen and K. Kaarniranta, “Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-κB signaling,” Cellular Signalling, vol. 22, no. 4, pp. 573–577, 2010.
[74]
S. Schlottmann, F. Buback, B. Stahl et al., “Prolonged classical NF-κB activation prevents autophagy upon E. coli stimulation in vitro: a potential resolving mechanism of inflammation,” Mediators of Inflammation, vol. 2008, Article ID 725854, 2008.
[75]
F. Zhou, Y. Yang, and D. Xing, “Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis,” FEBS Journal, vol. 278, no. 3, pp. 403–413, 2011.
[76]
E. Zalckvar, H. Berissi, L. Mizrachy et al., “DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy,” EMBO Reports, vol. 10, no. 3, pp. 285–292, 2009.
[77]
Y. K. Han, T. K. Ha, Y. G. Kim, and G. M. Lee, “Bcl-xL overexpression delays the onset of autophagy and apoptosis in hyperosmotic recombinant Chinese hamster ovary cell cultures,” Journal of Biotechnology, vol. 156, no. 1, pp. 52–55, 2011.
[78]
X. D. Zhang, Y. Wang, J. C. Wu et al., “Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum,” Journal of Neuroscience Research, vol. 87, no. 16, pp. 3600–3610, 2009.
[79]
M. Tamatani, Y. H. Che, H. Matsuzaki et al., “Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFκB activation in primary hippocampal neurons,” The Journal of Biological Chemistry, vol. 274, no. 13, pp. 8531–8538, 1999.
[80]
C. Chen, L. C. Edelstein, and C. Gélinas, “The Rel/NF-κb family directly activates expression of the apoptosis inhibitor BCl-x(L),” Molecular and Cellular Biology, vol. 20, no. 8, pp. 2687–2695, 2000.
[81]
J. N. Glasgow, T. Wood, and J. R. Perez-Polo, “Identification and characterization of nuclear factor κB binding sites in the murine bcl-x promoter,” Journal of Neurochemistry, vol. 75, no. 4, pp. 1377–1389, 2000.
[82]
S. D. Catz and J. L. Johnson, “Transcriptional regulation of bcl-2 by nuclear factor κB and its significance in prostate cancer,” Oncogene, vol. 20, no. 50, pp. 7342–7351, 2001.
[83]
P. Viatour, M. Bentires-Alj, A. Chariot et al., “NF-κB2/p100 induces Bcl-2 expression,” Leukemia, vol. 17, no. 7, pp. 1349–1356, 2003.
[84]
L. C. Edelstein, L. Lagos, M. Simmons, H. Tirumalai, and C. Gélinas, “NF-κB-dependent assembly of an enhanceosome-like complex on the promoter region of apoptosis inhibitor Bfl-1/A1,” Molecular and Cellular Biology, vol. 23, no. 8, pp. 2749–2761, 2003.
[85]
M. Kathania, C. I. Raje, M. Raje, R. K. Dutta, and S. Majumdar, “Bfl-1/A1 acts as a negative regulator of autophagy in mycobacteria infected macrophages,” International Journal of Biochemistry and Cell Biology, vol. 43, no. 4, pp. 573–585, 2011.
[86]
N. C. Chang, M. Nguyen, M. Germain, and G. C. Shore, “Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1,” EMBO Journal, vol. 29, no. 3, pp. 606–618, 2010.
[87]
L. A. Kirshenbaum, “Bcl-2 intersects the NFκB signalling pathway and suppresses apoptosis in ventricular myocytes,” Clinical and Investigative Medicine, vol. 23, no. 5, pp. 322–330, 2000.
[88]
K. M. Regula, K. Ens, and L. A. Kirshenbaum, “IKKβ is required for Bcl-2-mediated NF-κB activation in ventricular myocytes,” The Journal of Biological Chemistry, vol. 277, no. 41, pp. 38676–38682, 2002.
[89]
L. Vereecke, R. Beyaert, and G. van Loo, “The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology,” Trends in Immunology, vol. 30, no. 8, pp. 383–391, 2009.
[90]
L. Amir-Zilberstein and R. Dikstein, “Interplay between E-box and NF-κB in regulation of A20 gene by DRB sensitivity-inducing factor (DSIF),” The Journal of Biological Chemistry, vol. 283, no. 3, pp. 1317–1323, 2008.
[91]
L. Verstrepen, K. Verhelst, G. van Loo, I. Carpentier, S. C. Ley, and R. Beyaert, “Expression, biological activities and mechanisms of action of A20 (TNFAIP3),” Biochemical Pharmacology, vol. 80, no. 12, pp. 2009–2020, 2010.
[92]
N. Shembade and E. W. Harhaj, “Regulation of NF-κB signaling by the A20 deubiquitinase,” Cellular & Molecular Immunology, vol. 9, no. 2, pp. 123–139, 2012.
[93]
B. Skaug, J. Chen, F. Du, J. He, A. Ma, and Z. J. Chen, “Direct, noncatalytical mechanism of IKK inhibition by A20,” Molecular Cell, vol. 44, no. 4, pp. 559–571, 2011.
[94]
C. Mauro, F. Pacifico, A. Lavorgna et al., “ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB,” The Journal of Biological Chemistry, vol. 281, no. 27, pp. 18482–18488, 2006.
[95]
N. Jounai, K. Kobiyama, M. Shiina, K. Ogata, K. J. Ishii, and F. Takeshita, “NLRP4 negatively regulates autophagic processes through an association with Beclin1,” Journal of Immunology, vol. 186, no. 3, pp. 1646–1655, 2011.
[96]
K. Schroder and J. Tschopp, “The Inflammasomes,” Cell, vol. 140, no. 6, pp. 821–832, 2010.
[97]
F. G. Bauernfeind, G. Horvath, A. Stutz et al., “Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression,” Journal of Immunology, vol. 183, no. 2, pp. 787–791, 2009.
[98]
C. S. Shi, K. Shenderov, N. N. Huang et al., “Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction,” Nature Immunology, vol. 13, no. 3, pp. 255–263, 2012.
[99]
J. M. Bruey, N. Bruey-Sedano, F. Luciano et al., “Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1,” Cell, vol. 129, no. 1, pp. 45–56, 2007.
[100]
B. Faustin, Y. Chen, D. Zhai et al., “Mechanism of Bcl-2 and Bcl-XL inhibition of NLRP1 inflammasome: loop domain-dependent suppression of ATP binding and oligomerization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 10, pp. 3935–3940, 2009.
[101]
R. Scherz-Shouval and Z. Elazar, “Regulation of autophagy by ROS: physiology and pathology,” Trends in Biochemical Sciences, vol. 36, no. 1, pp. 30–38, 2011.
[102]
J. Lee, S. Giordano, and J. Zhang, “Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling,” Biochemical Journal, vol. 441, no. 2, pp. 523–540, 2012.
[103]
A. Pautz, J. Art, S. Hahn, S. Nowag, C. Voss, and H. Kleinert, “Regulation of the expression of inducible nitric oxide synthase,” Nitric Oxide, vol. 23, no. 1, pp. 75–93, 2010.
[104]
S. Sarkar, V. I. Korolchuk, M. Renna et al., “Complex inhibitory effects of nitric oxide on autophagy,” Molecular Cell, vol. 43, no. 1, pp. 19–32, 2011.
[105]
S. Alers, A. S. L？ffler, S. Wesselborg, and B. Stork, “Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks,” Molecular and Cellular Biology, vol. 32, no. 1, pp. 2–11, 2012.
[106]
N. M. Mazure and J. Pouysségur, “Hypoxia-induced autophagy: cell death or cell survival?” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 177–180, 2010.
[107]
G. Chinnadurai, S. Vijayalingam, and S. B. Gibson, “BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions,” Oncogene, vol. 27, no. 1, supplement, pp. S114–S127, 2008.
[108]
X. Feng, X. Liu, W. Zhang, and W. Xiao, “p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death,” EMBO Journal, vol. 30, no. 16, pp. 3397–3415, 2011.
[109]
H. Gang, R. Dhingra, Y. Wang, W. Mughal, J. W. Gordon, and L. A. Kirshenbaum, “Epigenetic regulation of E2F-1-dependent Bnip3 transcription and cell death by nuclear factor-κB and histone deacetylase-1,” Pediatric Cardiology, vol. 32, no. 3, pp. 263–266, 2011.
[110]
D. Baetz, K. M. Regula, K. Ens et al., “Nuclear factor-κB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes,” Circulation, vol. 112, no. 24, pp. 3777–3785, 2005.
[111]
J. Shaw, N. Yurkova, T. Zhang et al., “Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20734–20739, 2008.
[112]
R. Singh and A. M. Cuervo, “Autophagy in the cellular energetic balance,” Cell Metabolism, vol. 13, no. 5, pp. 495–504, 2011.
[113]
S. Pattingre, C. Bauvy, S. Carpentier, T. Levade, B. Levine, and P. Codogno, “Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy,” The Journal of Biological Chemistry, vol. 284, no. 5, pp. 2719–2728, 2009.
[114]
S. Papa, C. Bubici, F. Zazzeroni et al., “The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease,” Cell Death and Differentiation, vol. 13, no. 5, pp. 712–729, 2006.
[115]
C. Bubici, S. Papa, C. G. Pham, F. Zazzeroni, and G. Franzoso, “The NF-κB-mediated control of ROS and JNK signaling,” Histology and Histopathology, vol. 21, no. 1–3, pp. 69–80, 2006.
[116]
H. Nakano, A. Nakajima, S. Sakon-Komazawa, J. H. Piao, X. Xue, and K. Okumura, “Reactive oxygen species mediate crosstalk between NF-κB and JNK,” Cell Death and Differentiation, vol. 13, no. 5, pp. 730–737, 2006.
[117]
J. Liu and A. Lin, “Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases,” Oncogene, vol. 26, no. 22, pp. 3267–3278, 2007.
[118]
M. M. Lipinski, B. Zheng, T. Lu et al., “Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 32, pp. 14164–14169, 2010.
[119]
M. J. Morgan and Z. G. Liu, “Crosstalk of reactive oxygen species and NF-κB signaling,” Cell Research, vol. 21, no. 1, pp. 103–115, 2011.
[120]
M. C. Maiuri, E. Tasdemir, A. Criollo et al., “Control of autophagy by oncogenes and tumor suppressor genes,” Cell Death and Differentiation, vol. 16, no. 1, pp. 87–93, 2009.
[121]
E. L. Eskelinen, “The dual role of autophagy in cancer,” Current Opinion in Pharmacology, vol. 11, no. 4, pp. 294–300, 2011.
[122]
G. M. Balaburski, R. D. Hontz, and M. E. Murphy, “P53 and ARF: unexpected players in autophagy,” Trends in Cell Biology, vol. 20, no. 6, pp. 363–369, 2010.
[123]
J. A. DiDonato, F. Mercurio, and M. Karin, “NF-κB and the link between inflammation and cancer,” Immunological Reviews, vol. 246, no. 1, pp. 379–400, 2012.
[124]
P. Ak and A. J. Levine, “p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism,” FASEB Journal, vol. 24, no. 10, pp. 3643–3652, 2010.
[125]
K. M. Ryan, “P53 and autophagy in cancer: guardian of the genome meets guardian of the proteome,” European Journal of Cancer, vol. 47, no. 1, pp. 44–50, 2011.
[126]
C. Franceschi, S. Valensin, M. Bonafè et al., “The network and the remodeling theories of aging: historical background and new perspectives,” Experimental Gerontology, vol. 35, no. 6-7, pp. 879–896, 2000.
[127]
A. Larbi, C. Franceschi, D. Mazzatti, R. Solana, A. Wikby, and G. Pawelec, “Aging of the immune system as a prognostic factor for human longevity,” Physiology, vol. 23, no. 2, pp. 64–74, 2008.
[128]
J. P. de Magalh？es, J. Curado, and G. M. Church, “Meta-analysis of age-related gene expression profiles identifies common signatures of aging,” Bioinformatics, vol. 25, no. 7, pp. 875–881, 2009.
[129]
W. R. Swindell, “Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse,” BMC Genomics, vol. 10, article 585, 2009.
[130]
K. S. Krabbe, M. Pedersen, and H. Bruunsgaard, “Inflammatory mediators in the elderly,” Experimental Gerontology, vol. 39, no. 5, pp. 687–699, 2004.
[131]
T. Singh and A. B. Newman, “Inflammatory markers in population studies of aging,” Ageing Research Reviews, vol. 10, no. 3, pp. 319–329, 2011.
[132]
M. Helenius, M. H？nninen, S. K. Lehtinen, and A. Salminen, “Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-κB,” Biochemical Journal, vol. 318, no. 2, pp. 603–608, 1996.
[133]
N. F. L. Spencer, M. E. Poynter, S. Y. Im, and R. A. Daynes, “Constitutive activation of NF-κB in an animal model of aging,” International Immunology, vol. 9, no. 10, pp. 1581–1588, 1997.
[134]
M. Helenius, S. Kyrylenko, P. Vehvil？inen, and A. Salminen, “Characterization of aging-associated up-regulation of constitutive nuclear factor-κB binding activity,” Antioxidants and Redox Signaling, vol. 3, no. 1, pp. 147–156, 2001.
[135]
A. S. Adler, S. Sinha, T. L. A. Kawahara, J. Y. Zhang, E. Segal, and H. Y. Chang, “Motif module map reveals enforcement of aging by continual NF-κB activity,” Genes and Development, vol. 21, no. 24, pp. 3244–3257, 2007.
[136]
D. C. Rubinsztein, G. Marino, and G. Kroemer, “Autophagy and aging,” Cell, vol. 146, no. 5, pp. 682–695, 2011.
[137]
E. Wang, “Regulation of apoptosis resistance and ontogeny of age-dependent diseases,” Experimental Gerontology, vol. 32, no. 4-5, pp. 471–484, 1997.
[138]
N. Bye, M. Zieba, N. G. Wreford, and N. R. Nichols, “Resistance of the dentate gyrus to induced apoptosis during ageing is associated with increases in transforming growth factor-β1 messenger RNA,” Neuroscience, vol. 105, no. 4, pp. 853–862, 2001.
[139]
Y. Zhang and B. Herman, “Ageing and apoptosis,” Mechanisms of Ageing and Development, vol. 123, no. 4, pp. 245–260, 2002.
[140]
N. Kavathia, A. Jain, J. Walston, B. A. Beamer, and N. S. Fedarko, “Serum markers of apoptosis decrease with age and cancer stage,” Aging, vol. 1, no. 7, pp. 652–663, 2009.
[141]
A. Salminen, J. Ojala, and K. Kaarniranta, “Apoptosis and aging: increased resistance to apoptosis enhances the aging process,” Cellular and Molecular Life Sciences, vol. 68, no. 6, pp. 1021–1031, 2011.
[142]
D. Monti, S. Salvioli, M. Capri et al., “Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians,” Mechanisms of Ageing and Development, vol. 121, no. 1–3, pp. 239–250, 2001.
[143]
J. Krishnamurthy, C. Torrice, M. R. Ramsey et al., “Ink4a/Arf expression is a biomarker of aging,” Journal of Clinical Investigation, vol. 114, no. 9, pp. 1299–1307, 2004.
[144]
J. C. Jeyapalan, M. Ferreira, J. M. Sedivy, and U. Herbig, “Accumulation of senescent cells in mitotic tissue of aging primates,” Mechanisms of Ageing and Development, vol. 128, no. 1, pp. 36–44, 2007.
[145]
P. J. Rochette and D. E. Brash, “Progressive apoptosis resistance prior to senescence and control by the anti-apoptotic protein BCL-xL,” Mechanisms of Ageing and Development, vol. 129, no. 4, pp. 207–214, 2008.
[146]
J. Campisi, J. K. Andersen, P. Kapahi, and S. Melov, “Cellular senescence: a link between cancer and age-related degenerative disease?” Seminars in Cancer Biology, vol. 21, no. 6, pp. 354–359, 2011.
[147]
A. Salminen, A. Kauppinen, and K. Kaarniranta, “Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP),” Cellular Signaling, vol. 24, no. 4, pp. 835–845, 2012.
[148]
H. T. Kang, K. B. Lee, S. Y. Kim, H. R. Choi, and S. C. Park, “Autophagy impairment induces premature senescence in primary human fibroblasts,” PLoS ONE, vol. 6, no. 8, article e23367, 2011.
[149]
A. R. J. Young, M. Narita, M. Ferreira et al., “Autophagy mediates the mitotic senescence transition,” Genes and Development, vol. 23, no. 7, pp. 798–803, 2009.
[150]
M. Elgendy, C. Sheridan, G. Brumatti, and S. J. Martin, “Oncogenic ras-induced expression of noxa and beclin-1 promotes autophagic cell death and limits clonogenic survival,” Molecular Cell, vol. 42, no. 1, pp. 23–35, 2011.
[151]
U. T. Brunk and A. Terman, “The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis,” European Journal of Biochemistry, vol. 269, no. 8, pp. 1996–2002, 2002.
[152]
T. Strowig, J. Henao-Mejia, E. Elinav, and R. Flavell, “Inflammasomes in health and disease,” Nature, vol. 481, no. 7381, pp. 278–286, 2012.
[153]
J. Tschopp and K. Schroder, “NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?” Nature Reviews Immunology, vol. 10, no. 3, pp. 210–215, 2010.
[154]
J. Moscat, P. Rennert, and M. T. Diaz-Meco, “PKCζ at the crossroad of NF-κB and Jak1/Stat6 signaling pathways,” Cell Death and Differentiation, vol. 13, no. 5, pp. 702–711, 2006.
[155]
N. Festjens, T. Vanden Berghe, S. Cornelis, and P. Vandenabeele, “RIP1, a kinase on the crossroads of a cell's decision to live or die,” Cell Death and Differentiation, vol. 14, no. 3, pp. 400–410, 2007.
[156]
T. Johansen and T. Lamark, “Selective autophagy mediated by autophagic adapter proteins,” Autophagy, vol. 7, no. 3, pp. 279–296, 2011.
[157]
Y. Hua, Y. Zhang, A. F. Ceylan-Isik, L. E. Wold, J. M. Nunn, and J. Ren, “Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy,” Basic Research in Cardiology, vol. 106, no. 6, pp. 1173–1191, 2011.
[158]
S. E. Wohlgemuth, D. Julian, D. E. Akin et al., “Autophagy in the heart and liver during normal aging and calorie restriction,” Rejuvenation Research, vol. 10, no. 3, pp. 281–292, 2007.
[159]
A. Migheli, P. Cavalla, R. Piva, M. T. Giordana, and D. Schiffer, “Bcl-2 protein expression in aged brain and neurodegenerative diseases,” NeuroReport, vol. 5, no. 15, pp. 1906–1908, 1994.
[160]
J. A. Kaufmann, P. C. Bickford, and G. Taglialatela, “Oxidative-stress-dependent up-regulation of Bcl-2 expression in the central nervous system of aged Fisher-344 rats,” Journal of Neurochemistry, vol. 76, no. 4, pp. 1099–1108, 2001.
[161]
T. Satou, B. J. Cummings, and C. W. Cotman, “Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer's disease brain increases with disease severity,” Brain Research, vol. 697, no. 1-2, pp. 35–43, 1995.
[162]
Y. Z. Xu, X. H. Deng, and M. Bentivoglio, “Differential response of apoptosis-regulatory Bcl-2 and Bax proteins to an inflammatory challenge in the cerebral cortex and hippocampus of aging mice,” Brain Research Bulletin, vol. 74, no. 5, pp. 329–335, 2007.
[163]
E. Wang, “Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved,” Cancer Research, vol. 55, no. 11, pp. 2284–2292, 1995.
[164]
T. Kumazaki, M. Sasaki, M. Nishiyama et al., “Life span shortening of normal fibroblasts by overexpression of BCL-2: a result of potent increase in cell death,” Experimental Cell Research, vol. 285, no. 2, pp. 299–308, 2003.
[165]
E. Crescenzi, G. Palumbo, and H. J. M. Brady, “Bcl-2 activates a programme of premature senescence in human carcinoma cells,” Biochemical Journal, vol. 375, no. 2, pp. 263–274, 2003.
[166]
J. J. Lee, J. H. Lee, Y. G. Ko, S. I. Hong, and J. S. Lee, “Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species,” Oncogene, vol. 29, no. 4, pp. 561–575, 2010.
[167]
A. Agresti, R. Lupo, M. E. Bianchi, and S. Müller, “HMGB1 interacts differentially with members of the Rel family of transcription factors,” Biochemical and Biophysical Research Communications, vol. 302, no. 2, pp. 421–426, 2003.
[168]
R. Kang, K. M. Livesey, H. J. Zeh, M. T. Lotze, and D. Tang, “HMGB1: a novel Beclin 1-binding protein active in autophagy,” Autophagy, vol. 6, no. 8, pp. 1209–1211, 2010.
[169]
M. ？tros, “HMGB proteins: interactions with DNA and chromatin,” Biochimica et Biophysica Acta, vol. 1799, no. 1-2, pp. 101–113, 2010.
[170]
D. Tang, R. Kang, H. J. Zeh, and M. T. Lotze, “High-mobility group box 1, oxidative stress, and disease,” Antioxidants and Redox Signaling, vol. 14, no. 7, pp. 1315–1335, 2011.
[171]
D. Tang, R. Kang, K. M. Livesey et al., “Endogenous HMGB1 regulates autophagy,” Journal of Cell Biology, vol. 190, no. 5, pp. 881–892, 2010.
[172]
L. van de Walle, T. D. Kanneganti, and M. Lamkanfi, “HMGB1 release by inflammasomes,” Virulence, vol. 2, no. 2, pp. 162–165, 2011.
[173]
S. Prasad and M. K. Thakur, “Distribution of high mobility group proteins in different tissues of rats during aging,” Biochemistry International, vol. 20, no. 4, pp. 687–695, 1990.
[174]
Y. Enokido, A. Yoshitake, H. Ito, and H. Okazawa, “Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain,” Biochemical and Biophysical Research Communications, vol. 376, no. 1, pp. 128–133, 2008.
[175]
D. Tang, R. Kang, H. J. Zeh, and M. T. Lotze, “High-mobility group box 1 and cancer,” Biochimica et Biophysica Acta, vol. 1799, no. 1-2, pp. 131–140, 2010.
[176]
D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of gerontology, vol. 11, no. 3, pp. 298–300, 1956.
[177]
G. Petrovski and D. K. Das, “Does autophagy take a front seat in lifespan extension?” Journal of Cellular and Molecular Medicine, vol. 14, no. 11, pp. 2543–2551, 2010.
[178]
S. Hekimi, J. Lapointe, and Y. Wen, “Taking a “good” look at free radicals in the aging process,” Trends in Cell Biology, vol. 21, no. 10, pp. 569–576, 2011.
[179]
M. Ristow and S. Schmeisser, “Extending life span by increasing oxidative stress,” Free Radical Biology and Medicine, vol. 51, no. 2, pp. 327–336, 2011.
[180]
F. Bauernfeind, E. Bartok, A. Rieger, L. Franchi, G. Nú？ez, and V. Hornung, “Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome,” Journal of Immunology, vol. 187, no. 2, pp. 613–617, 2011.
[181]
X. Zhang, G. Zhang, H. Zhang, M. Karin, H. Bai, and D. Cai, “Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity,” Cell, vol. 135, no. 1, pp. 61–73, 2008.
[182]
S. Purkayastha, H. Zhang, G. Zhang, Z. Ahmed, Y. Wang, and D. Cai, “Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 7, pp. 2939–2944, 2011.
[183]
D. Cai and T. Liu, “Inflammatory cause of metabolic syndrome via brain stress and NF-κB,” Aging (Albany NY), vol. 4, no. 2, pp. 98–115, 2012.
[184]
S. Gerondakis, R. Grumont, R. Gugasyan et al., “Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models,” Oncogene, vol. 25, no. 51, pp. 6781–6799, 2006.
[185]
W. R. Swindell, A. Johnston, L. Sun et al., “Meta-profiles of gene expression during aging: limited similarities between mouse and human and an unexpectedly decreased inflammatory signature,” PLoS ONE, vol. 7, 3, article e33204, 2012.
