STING-mediated degradation of IFI16 negatively regulates apoptosis by inhibiting p53 phosphorylation at serine 392

Abstract

Interferon-γ–inducible factor 16 (IFI16) triggers stimulator of interferon (IFN) genes (STING)–dependent type I IFN production during host antiviral immunity and facilitates p53-dependent apoptosis during suppressing tumorigenesis. We have previously reported that STING-mediated IFI16 degradation negatively regulates type I IFN production. However, it is unknown whether STING also suppresses IFI16/p53-dependent apoptosis via degradation of IFI16. Here, our results from flow cytometry apoptosis detection and immunoblot assays show that IFI16 and nutlin-3, a p53 pathway activator, synergistically induce apoptosis in U2OS and A549 cells. Protein kinase R–triggered phosphorylation of p53 at serine 392 is critical for the IFI16-p53–dependent apoptosis. However, overexpression of STING suppresses p53 serine 392 phosphorylation, p53 transcriptional activity, expression of p53 target genes, and p53-dependent mitochondrial depolarization and apoptosis. In summary, our current study demonstrates that STING-mediated IFI16 degradation negatively regulates IFI16-mediated p53-dependent apoptosis in osteosarcoma and non–small cell lung cancer cells, which suggests a protumorigenic role for STING in certain cancer types because of its potent ability to degrade upstream IFI16. Interferon-γ–inducible factor 16 (IFI16) triggers stimulator of interferon (IFN) genes (STING)–dependent type I IFN production during host antiviral immunity and facilitates p53-dependent apoptosis during suppressing tumorigenesis. We have previously reported that STING-mediated IFI16 degradation negatively regulates type I IFN production. However, it is unknown whether STING also suppresses IFI16/p53-dependent apoptosis via degradation of IFI16. Here, our results from flow cytometry apoptosis detection and immunoblot assays show that IFI16 and nutlin-3, a p53 pathway activator, synergistically induce apoptosis in U2OS and A549 cells. Protein kinase R–triggered phosphorylation of p53 at serine 392 is critical for the IFI16-p53–dependent apoptosis. However, overexpression of STING suppresses p53 serine 392 phosphorylation, p53 transcriptional activity, expression of p53 target genes, and p53-dependent mitochondrial depolarization and apoptosis. In summary, our current study demonstrates that STING-mediated IFI16 degradation negatively regulates IFI16-mediated p53-dependent apoptosis in osteosarcoma and non–small cell lung cancer cells, which suggests a protumorigenic role for STING in certain cancer types because of its potent ability to degrade upstream IFI16. Interferon (IFN)-γ–inducible factor 16 (IFI16) is a member of the IFN-inducible PYHIN protein family of nuclear proteins and considered as an important DNA sensor in recognizing pathogenic DNA (1Unterholzner L. Keating S.E. Baran M. Horan K.A. Jensen S.B. Sharma S. Sirois C.M. Jin T. Latz E. Xiao T.S. Fitzgerald K.A. Paludan S.R. Bowie A.G. IFI16 is an innate immune sensor for intracellular DNA.Nat. Immunol. 2010; 11: 997-1004Crossref PubMed Scopus (1092) Google Scholar). It contains a PYRIN domain (PYD) at the N-terminus and two conserved hematopoietic expression, IFN-inducible, and nuclear location (HIN) domains (HIN-A and HIN-B) at the C-terminus (2Choubey D. Duan X. Dickerson E. Ponomareva L. Panchanathan R. Shen H. Srivastava R. Interferon-inducible p200-family proteins as novel sensors of cytoplasmic DNA: Role in inflammation and autoimmunity.J. Interferon Cytokine Res. 2010; 30: 371-380Crossref PubMed Scopus (79) Google Scholar, 3Dawson M.J. Trapani J.A. HIN-200: A novel family of IFN-inducible nuclear proteins expressed in leukocytes.J. Leukoc. Biol. 1996; 60: 310-316Crossref PubMed Scopus (41) Google Scholar). The PYD of IFI16 mediates homotypic and heterotypic protein–protein interaction, which is responsible for signaling transduction (4Stehlik C. The PYRIN domain in signal transduction.Curr. Protein Pept. Sci. 2007; 8: 293-310Crossref PubMed Scopus (20) Google Scholar). IFI16 interacts with the adaptor molecule apoptosis-associated speck like protein containing a caspase recruitment domain via the PYD–PYD interactions to form a functional inflammasome during Kaposi sarcoma–associated herpesvirus infection (5Kerur N. Veettil M.V. Sharma-Walia N. Bottero V. Sadagopan S. Otageri P. Chandran B. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.Cell Host Microbe. 2011; 9: 363-375Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 6Dowling J.K. O'Neill L.A. Biochemical regulation of the inflammasome.Crit. Rev. Biochem. Mol. Biol. 2012; 47: 424-443Crossref PubMed Scopus (98) Google Scholar). IFI16 also interacts with stimulator of IFN genes (STING) to activate the downstream TANK-binding kinase 1–IFN regulatory factory 3–IFN-β signaling axis via its PYD (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The C-terminal HIN-A and HIN-B domains have been implicated in DNA binding and mediating protein–protein interaction for transcriptional regulation (8Choubey D. Panchanathan R. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases.Ageing Res. Rev. 2016; 28: 27-36Crossref PubMed Scopus (32) Google Scholar). For example, HIN-A domain binds to the C-terminal region of p53, whereas the HIN-B domain binds to the core DNA-binding region of p53, which synergistically contributes to the effect of IFI16 on p53–DNA complex formation and transcriptional activation (9Liao J.C. Lam R. Brazda V. Duan S. Ravichandran M. Ma J. Xiao T. Tempel W. Zuo X. Wang Y.X. Chirgadze N.Y. Arrowsmith C.H. Interferon-inducible protein 16: Insight into the interaction with tumor suppressor p53.Structure. 2011; 19: 418-429Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In addition to the roles in DNA sensing and activating antiviral immunity, IFI16 negatively regulates tumorigenesis by interacting with p53 or inducing transcription of p53 (8Choubey D. Panchanathan R. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases.Ageing Res. Rev. 2016; 28: 27-36Crossref PubMed Scopus (32) Google Scholar, 9Liao J.C. Lam R. Brazda V. Duan S. Ravichandran M. Ma J. Xiao T. Tempel W. Zuo X. Wang Y.X. Chirgadze N.Y. Arrowsmith C.H. Interferon-inducible protein 16: Insight into the interaction with tumor suppressor p53.Structure. 2011; 19: 418-429Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 10Fujiuchi N. Aglipay J.A. Ohtsuka T. Maehara N. Sahin F. Su G.H. Lee S.W. Ouchi T. Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation.J. Biol. Chem. 2004; 279: 20339-20344Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). As a DNA damage amplifier, IFI16 interacts with p53, promotes p53 phosphorylation at serine 15 (Ser15), and thus participates in the accumulation and activation of p53 caused by DNA damage, which ultimately promotes p53-dependent apoptosis (8Choubey D. Panchanathan R. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases.Ageing Res. Rev. 2016; 28: 27-36Crossref PubMed Scopus (32) Google Scholar, 10Fujiuchi N. Aglipay J.A. Ohtsuka T. Maehara N. Sahin F. Su G.H. Lee S.W. Ouchi T. Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation.J. Biol. Chem. 2004; 279: 20339-20344Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Besides the Ser15 residue, the highly conserved residue, serine 392 (Ser392) (Ser389 in mice), is also a major phosphorylation site of p53. Ser392 phosphorylation is a common and integral event during p53 activation under diverse stimuli such as UV or the murine double minute 2 (MDM2)-p53 antagonist nutlin-3 treatment (11Bruins W. Bruning O. M.J. E. H. The of phosphorylation in p53 the expression of p53-dependent genes and the response to UV in Biol. 28: PubMed Scopus Google Scholar, of serine 392 in p53 is a common and integral event during p53 by diverse 2010; PubMed Scopus Google Scholar, S. Wang S. of the interaction to p53 A novel for cancer Rev. PubMed Scopus Google Scholar). protein kinase protein and protein kinase have been to responsible for p53 Ser392 phosphorylation S. M. of kinase with Google Scholar, S. The protein kinase with the tumor suppressor p53 protein and p53 on serine 392 in PubMed Scopus Google Scholar, C. Ma Y. Z. kinase mediates phosphorylation of p53 protein at serine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, it is unknown whether IFI16, the p53 facilitates protein Ser392 phosphorylation of p53 and p53-dependent apoptosis. signaling pathway important roles in immunity and tumor STING from tumor triggers a STING-mediated IFN response in to activate the response of M. Wang L. triggers a STING-mediated interferon response in to activate the cell Full Text Full Text PDF PubMed Scopus Google Scholar). and activate activity, with and of J. N. R. P. S. M. J. M. J. of STING with PubMed Scopus Google Scholar). STING such as and have been to induce in murine and cells, tumor on the murine and and induce tumor L. S.R. E. T. activation of STING in the tumor to potent and tumor and Rep. 11: Full Text Full Text PDF PubMed Scopus Google Scholar). However, as a potent type I IFN STING also promotes tumor and in a In accumulation with STING signaling from to and in N.Y. M. S. J. S. The DNA mediates DNA sensor host of cancer 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). STING activation is with tumor in the lung H. E. Huang L. R. D. STING promotes the of by via Res. 2016; PubMed Scopus Google Scholar). In cancer and lung from tumor to which activate and signaling in the and thus tumor Jin X. M. L. R. H. Xu J. by 2016; PubMed Scopus Google Scholar). study that STING negatively controls IFI16 expression by upstream IFI16 during antiviral immunity (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). As IFI16 with p53 to it to whether STING-mediated degradation of upstream IFI16 also suppresses IFI16-p53–dependent and whether STING a role of activating its downstream and In have that IFI16 promotes p53-dependent the of mitochondrial p53 Ser392 phosphorylation, p53 transcriptional activity, and expression of p53 target genes in osteosarcoma and cells. However, STING suppresses IFI16-mediated by upstream IFI16 have an pathway that STING a role in signaling in addition to in antiviral whether IFI16 regulates p53-dependent apoptosis in osteosarcoma cells, IFI16 in U2OS the a antagonist and p53 pathway activator, U2OS apoptosis in a A and However, of IFI16 the of apoptosis by nutlin-3 A and the of caspase a critical of also in the cells, whereas it highly induced in the which suggests that IFI16 and nutlin-3 synergistically induce and p53 to activate p53-dependent apoptosis. the and to the and treatment apoptosis in the whereas in the that in the IFI16 is an in cell types M.J. Trapani J.A. HIN-200: A novel family of IFN-inducible nuclear proteins expressed in leukocytes.J. Leukoc. Biol. 1996; 60: 310-316Crossref PubMed Scopus (41) Google Scholar, M.J. Trapani J.A. 16 a nuclear protein expression is induced by in cell Biochem. PubMed Scopus Google and that overexpression of IFI16 also apoptosis in U2OS and A549 cells, which is to the treatment and The the apoptosis induced by nutlin-3 treatment and overexpression of IFI16 in A549 overexpression of a downstream adaptor protein of IFI16 to induce during DNA infection (1Unterholzner L. Keating S.E. Baran M. Horan K.A. Jensen S.B. Sharma S. Sirois C.M. Jin T. Latz E. Xiao T.S. Fitzgerald K.A. Paludan S.R. Bowie A.G. IFI16 is an innate immune sensor for intracellular DNA.Nat. Immunol. 2010; 11: 997-1004Crossref PubMed Scopus (1092) Google apoptosis in U2OS In the cell in the or cells. of IFI16 cell in a whereas overexpression of STING cell in the A549 with a of nutlin-3, which induced apoptosis to the in A549 cells, the of IFI16 and STING in the regulation of cell also in the U2OS with nutlin-3 functional p53 signaling in the reported previously Srivastava E. of apoptosis in lung cancer by 2004; PubMed Scopus Google Scholar, Y. DNA pathway of lung cancer A549 and to J. Mol. Sci. 19: Scopus Google and that overexpression of IFI16 and STING apoptosis in the I and overexpression or of IFI16 facilitates p53-dependent apoptosis and cell whereas overexpression of STING suppresses p53-dependent apoptosis and cell during nutlin-3 is a of cell or and the of to apoptosis. the of and the of to in the F. L. of the mitochondrial the as a 2019; PubMed Google Scholar). whether the IFI16 or apoptosis from the in A549 or U2OS with nutlin-3, that the during nutlin-3 treatment at the which is to induce the expression of caspase and apoptosis of IFI16 the of in with nutlin-3 of in U2OS in the to the results from cells, overexpression of STING also the of in A549 with nutlin-3 at a of IFI16 or STING the of in p53 and The of is a event of p53-dependent apoptosis R. R. p53 regulates mitochondrial and apoptosis by J. PubMed Scopus Google Scholar). results the role of IFI16 and STING in the regulation of apoptosis. the roles of IFI16 and STING in the regulation of p53 signaling of a p53 to transcriptional treatment the p53 transcriptional in a in A549 A and of p53-dependent apoptosis J.C. in p53 to 2016; Full Text Full Text PDF PubMed Scopus Google also induced p53 transcriptional in U2OS treatment induced in the A549 with nutlin-3 of IFI16 the by nutlin-3 treatment in U2OS of IFI16 induced in the and of nutlin-3 whereas overexpression of STING as a transcription factor in the p53 regulatory by genes M. and of the p53 regulatory and 2019; PubMed Scopus Google Scholar, T. J.C. suppressor p53 is a transcriptional of the Full Text PDF PubMed Scopus Google Scholar, L. T. the nuclear and cytoplasmic of PubMed Scopus Google Scholar). target genes of apoptosis protein and induced in the of IFI16 the of by nutlin-3 in the or of overexpression of STING also the of and of which critical in the mitochondrial apoptosis in the U2OS with nutlin-3 and and In summary, have that IFI16 facilitates STING suppresses the p53-dependent the of p53 transcriptional activity, and the expression of p53 target genes in A549 and U2OS in the cells, in which the functional p53 signaling is of p53 by phosphorylation been to an important for p53 and activation W. of p53 Full Text Full Text PDF PubMed Scopus Google Scholar). whether the apoptosis induced by nutlin-3 from p53 phosphorylation, of the phosphorylation of p53 and that p53 induced in the U2OS with of nutlin-3 However, p53 in the that in of IFI16 Ser392 phosphorylation of p53 in and with of However, the Ser15 phosphorylation and p53 expression induced in cell and and We the protein of IFI16, p53, and STING in and cell expression of IFI16 and STING in U2OS A549 expressed the p53, IFI16, and STING the cell types The the IFI16, and p53 in the cell types a STING and signaling overexpression of STING the of IFI16 in tumor cell which p53 accumulation p53 in the and cells, which for the functional in the have been reported to responsible for Ser392 phosphorylation of p53, such as protein kinase and the protein kinase S. The protein kinase with the tumor suppressor p53 protein and p53 on serine 392 in PubMed Scopus Google Scholar, C. Ma Y. Z. kinase mediates phosphorylation of p53 protein at serine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We whether IFI16 or Ser392 phosphorylation of p53. results that overexpression of IFI16 binding IFI16 and interaction and and and of Ser392 phosphorylation of p53 in A549 IFI16 with the p53 and Ser392 phosphorylation of p53 as nutlin-3 treatment the overexpression of STING the Ser392 phosphorylation of p53 induced by nutlin-3 or treatment in the U2OS and overexpression of STING also Ser392 phosphorylation of p53 induced by nutlin-3 in A549 or by in and In that IFI16 and p53 in the and in the and which with apoptosis and of in cells. IFI16 or STING Ser392 phosphorylation of p53 and damage and IFI16 facilitates and STING suppresses Ser392 phosphorylation of p53 in U2OS and A549 cells, which suggests that p53 mediates the effect of IFI16 on the regulation of the of and p53 transcriptional the of Ser392 phosphorylation of p53 in the p53 and with a at serine 392 to and or treatment induced apoptosis in U2OS A and p53 expression apoptosis whereas the induced apoptosis in to a A and of p53 in the p53 expressed in the expressed cells, with of or p53 apoptosis in the that in p53 in IFI16 and caspase expression whereas caspase in the as a of a in Ser392 phosphorylation with the apoptosis and p53 transcriptional in the that in the and of the functional p53 signaling pathway in U2OS and cells, our results that the Ser392 phosphorylation of p53 induced by IFI16 is critical for the regulation of the of and p53 transcriptional study that STING facilitates IFI16 degradation via the (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). In U2OS cells, also that expressed STING the of apoptosis in the in the STING the IFI16 protein and also IFI16-p53–dependent apoptosis in the and and overexpression of STING the of in the in the STING expression and of IFI16 also the of and p53 target genes and expression, roles in mitochondrial apoptosis and an IFI16 that is to STING-mediated degradation (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google the Ser392 phosphorylation of p53, the of p53 target genes such as and and p53-dependent apoptosis in A549 In induced in the by IFI16 As a overexpression to apoptosis IFI16 in A549 In summary, our results have that IFI16 promotes p53-dependent the of Ser392 phosphorylation of p53, p53 transcriptional activity, and expression of p53 target genes in U2OS and A549 cells. However, STING IFI16-mediated by the degradation of the upstream IFI16 IFI16 is an important in antiviral immunity and tumorigenesis. of IFI16 expression is with and with of IFI16 in and with IFI16 in in the with Y. N. of in and of by PubMed Scopus Google Scholar). In of IFI16 and in the of with M. J. L. of to with of in Res. 2016; PubMed Scopus Google Scholar). In to the of IFI16 in or expression of IFI16 is with of of and N. Aglipay J.A. Ohtsuka T. Maehara N. Sahin F. Su G.H. Lee S.W. Ouchi T. Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation.J. Biol. Chem. 2004; 279: 20339-20344Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, H. J. D. Role of a member of the in cellular PubMed Scopus Google Scholar, H. H. Y. Y. H. S. of and response to PubMed Google Scholar, Y. J. L. J.C. IFI16 and cell of and tumor 2007; PubMed Scopus Google Scholar). expression of the murine of IFI16, is with in murine and expression of IFI16 is with of with H. H. Y. Y. H. S. of and response to PubMed Google Scholar). IFI16 expression is to during antiviral of IFI16 triggers antiviral immunity, by the of host innate immunity, which to degradation of IFI16 by protein complex antiviral immunity and from (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). However, the of IFI16 suppresses p53-dependent which to tumorigenesis. current study a role of STING-mediated degradation of IFI16 in it is for the host to during antiviral The p53 tumor suppressor protein a major role in cellular response to DNA damage and of p53 by phosphorylation at triggers apoptosis pathway and tumorigenesis B. D. the p53 PubMed Scopus Google Scholar). The C-terminal phosphorylation of p53 is of its and the C-terminal phosphorylation region M. of p53 and by Biol. 19: PubMed Scopus Google Scholar, p53 C-terminal phosphorylation by and participates in the regulation of C-terminal Biol. 16: PubMed Scopus Google Scholar). Ser392 is highly conserved in of p53 at Ser392 is for the suppressor DNA and transcriptional of p53 (11Bruins W. Bruning O. M.J. E. H. The of phosphorylation in p53 the expression of p53-dependent genes and the response to UV in Biol. 28: PubMed Scopus Google Scholar, of serine 392 in p53 is a common and integral event during p53 by diverse 2010; PubMed Scopus Google Scholar, M. of phosphorylation of p53 on of from p53 1996; Google Scholar). In Ser392 phosphorylation p53 mitochondrial and apoptosis in lung C. B. O. P. 392 phosphorylation p53 mitochondrial and PubMed Scopus (32) Google Scholar). with synergistically p53 induce apoptosis M. M. B. M. activation of p53 by and is with the of and of innate PubMed Scopus Google Scholar). In our have that nutlin-3 is to p53-dependent apoptosis and to induce IFI16 IFI16 to p53, which Ser392 phosphorylation of p53, in the of of IFI16 the transcriptional of p53 and the of p53 target genes, such as and which responsible for apoptosis. of is in the cells. Besides the of Ser392 phosphorylation in inducing our results that IFI16 promotes Ser392 phosphorylation of p53 and p53-dependent apoptosis via the which p53 target genes and to mitochondrial However, the maximal activation of p53 synergistically by phosphorylation as the at Ser392 p53-dependent STING have been in cancer and J. N. R. P. S. M. J. M. J. of STING with PubMed Scopus Google Scholar, L. S.R. E. T. activation of STING in the tumor to potent and tumor and Rep. 11: Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. E. P. W. L. cancer to Scopus Google of STING signaling in tumorigenesis. have the role of STING by activating its downstream or signaling H. E. Huang L. R. D. STING promotes the of by via Res. 2016; PubMed Scopus Google Scholar, Jin X. M. L. R. H. Xu J. by 2016; PubMed Scopus Google Scholar). the upstream DNA sensor of into the and tumor H. H. Wu X. Ma D. Wu J. Wang L. Y. Y. Zhu C. R. P. F. suppresses DNA and promotes PubMed Scopus Google Scholar). IFI16 with to activate STING during DNA sensing in J. Bowie A.G. L. IFI16 and in the activation of STING during DNA sensing in 8: PubMed Scopus Google Scholar). results have that STING-mediated IFI16 degradation suppresses p53 and p53-dependent apoptosis in U2OS in cells, that STING also tumorigenesis by negatively the upstream apoptosis The of STING-mediated IFI16 degradation in tumorigenesis by the tumor and tumor that DNA from the of such as and Kaposi sarcoma–associated herpesvirus is by IFI16 (5Kerur N. Veettil M.V. Sharma-Walia N. Bottero V. Sadagopan S. Otageri P. Chandran B. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.Cell Host Microbe. 2011; 9: 363-375Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, M. C. S. Chandran B. S. M. The nuclear DNA sensor IFI16 acts as a factor for of the PubMed Scopus Google Scholar, M. B. L. Chandran B. protein 16 (IFI16) is for the of J. PubMed Scopus Google of IFI16 by proteins or host such as STING IFI16-p53–dependent which to tumorigenesis. STING-mediated degradation of IFI16 the host to production and during antiviral immunity However, regulation also p53-dependent which for the of DNA family binding and have been N. J. F. R. B. M. D. of the antagonist on the pathway in with or 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. N. J. D. F. C. C. B. of a potent and in Chem. PubMed Scopus Google Scholar, J. S. O. C. interaction suppresses tumor in cell lung cancer Full Text Full Text PDF PubMed Scopus Google Scholar). IFI16 induced by DNA or transcriptional current that the or target antagonist a in like osteosarcoma or with STING expression which p53-dependent tumor cell apoptosis. study also an to tumorigenesis during tumor that IFI16 or p53, via the to IFI16 degradation with family antagonist A549 and from osteosarcoma U2OS cells, and cell lung cancer cell from the of of and by of A549 and in and the cell in with and at and For apoptosis and mitochondrial A549 and with nutlin-3 into the and (Ser392) from from (Ser392) caspase and from and from and from and from from from and nutlin-3 from U2OS IFI16 O. E. X. T. D. F. in PubMed Scopus Google Scholar, O. F. and for 11: PubMed Scopus Google Scholar). IFI16 into the a The the two by with the and and to U2OS in the of with at of cell and to and to the of IFI16 expression and the of cell The STING on the and U2OS cell In the with a into U2OS cells. with at of and to to the expression of STING of the IFI16, and p53 from of The by a of and p53 as by The in the study (7Li D. Wu R. Guo W. Xie L. Qiao Z. Chen S. Zhu J. Huang C. Huang J. Chen B. Qin Y. Xu F. Ma F. STING-mediated IFI16 degradation negatively controls type I interferon production.Cell Rep. 2019; 29: 1249-1260.e1244Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The of by DNA and of with into cell to the into and at the of into U2OS at the of 2 into at the of with nutlin-3, or as in the For the of in cells, cell as in the by and by to the is with a to in with apoptosis caused by mitochondrial depolarization or the with The of on an The of cellular by an in the cell For cell U2OS cells, A549 cells, or as in the by and by flow cytometry and to the as on an in and the with or nutlin-3 into the for the and containing to of the the for 2 and the at a the from and DNA the on a The expression of genes to the protein by by the PubMed Scopus Google Scholar). The for from X. Wang H. B. A for expression Res. 2012; PubMed Scopus Google and cell in and with For phosphorylation the with The cell to and immunoblot with and the The by on or by whether nutlin-3 and IFI16 to mitochondrial for mitochondrial to the the and two with The into on and the with and by or for A549 or U2OS on for and with for the and with or with with to of the for and the with and by a the into for In to or Ser392 phosphorylation on p53. A549 on for and with for The and with (Ser392) and In the of and signal to the the two in the a signal on a the into interaction by for and for A549 or U2OS cell in at a of and for The with a of p53 and the with with or or in the and the to the The of in as with with in considered and the in the and contains The that have of with the of We the from of of by the of and of and and of for of and and the for of F. M. D. L. and L. X. D. L. and S. M. D. L. and F. M. D. L. Z. J. F. S. L. and H. Y. D. L. D. L. and F. M. and L. X. and Z. F. Y. S. and F. M. with

Topics & Concepts