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Non-canonical NF-?B Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy.

ABSTRACT: The NF-?B pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-?B pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-?B pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-?B deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-?B signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-?B pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-?B pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-?B pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.

SUBMITTER: Hou Y

PROVIDER: S-EPMC6775781 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy.

Hou Yuzhu Y Liang Hua H Rao Enyu E Zheng Wenxin W Huang Xiaona X Deng Liufu L Zhang Yuan Y Yu Xinshuang X Xu Meng M Mauceri Helena H Arina Ainhoa A Weichselbaum Ralph R RR Fu Yang-Xin YX

Immunity 20180828 3

The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendri ...[more]

PMID: 30170810

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Project description:STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor ?B (NF-?B) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in response to STING activation by double-stranded DNA (dsDNA). Furthermore, TANK-binding kinase 1 (TBK1) associated with STING was found to facilitate dsDNA-mediated canonical activation of NF-?B as well as IRF3 to promote proinflammatory gene transcription. The triggering of NF-?B function was noted to require TRAF6 activation. Our findings detail a novel dsDNA-mediated NF-?B activation pathway facilitated through a STING-TRAF6-TBK1 axis and suggest a target for therapeutic intervention to plausibly stimulate antiviral activity or, alternatively, avert dsDNA-mediated inflammatory disease.The IKK complex, which is composed of two catalytic subunits, IKK? and IKK?, has been suggested to be essential for the activation of canonical NF-?B signaling in response to various stimuli, including cytokines (e.g., interleukin-1? [IL-1?] and tumor necrosis factor alpha [TNF-?]), Toll-like receptor (TLR) ligands (e.g., lipopolysaccharide [LPS]), and dsRNAs derived from viruses, or a synthetic analog. STING has been identified as a critical signaling molecule required for the detection of cytosolic dsDNAs derived from pathogens and viruses. However, little is known about how cytosolic dsDNA triggers NF-?B signaling. In the present study, we demonstrate that TBK1, identified as an IKK-related kinase, may predominantly control the activation of NF-?B in response to dsDNA signaling via STING through the IKK?? activation loop. Thus, our results establish TBK1 as a downstream kinase controlling dsDNA-mediated IRF3 and NF-?B signaling dependent on STING.

Dataset Information

Non-canonical NF-?B Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy.

Publications

Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy.

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