RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis
Abstract Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling...
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1334 |
| _version_ | 1797771173252038656 |
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| author | Xufei Zhang Jie Wu Qinjie Liu Xuanheng Li Yiyu Yang Lei Wu Xiuwen Wu Yun Zhao Jianan Ren |
| author_facet | Xufei Zhang Jie Wu Qinjie Liu Xuanheng Li Yiyu Yang Lei Wu Xiuwen Wu Yun Zhao Jianan Ren |
| author_sort | Xufei Zhang |
| collection | DOAJ |
| description | Abstract Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT‐29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL‐mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro‐necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA‐induced intestinal injury and sepsis. Conclusions These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING‐driven inflammatory diseases. |
| first_indexed | 2024-03-12T21:33:38Z |
| format | Article |
| id | doaj.art-8819603769c74e47918dad05879d4653 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-03-12T21:33:38Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-8819603769c74e47918dad05879d46532023-07-27T15:20:29ZengWileyClinical and Translational Medicine2001-13262023-07-01137n/an/a10.1002/ctm2.1334RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsisXufei Zhang0Jie Wu1Qinjie Liu2Xuanheng Li3Yiyu Yang4Lei Wu5Xiuwen Wu6Yun Zhao7Jianan Ren8Research Institute of General Surgery, Jinling Hospital, School of Medicine Southeast University Nanjing ChinaResearch Center of Surgery, BenQ Medical Center the Affiliated BenQ Hospital of Nanjing Medical University Nanjing ChinaResearch Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School Nanjing University NanjingChinaResearch Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School Nanjing University NanjingChinaResearch Institute of General Surgery, Jinling Hospital, School of Medicine Southeast University Nanjing ChinaResearch Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School Nanjing University NanjingChinaResearch Institute of General Surgery, Jinling Hospital, School of Medicine Southeast University Nanjing ChinaResearch Center of Surgery, BenQ Medical Center the Affiliated BenQ Hospital of Nanjing Medical University Nanjing ChinaResearch Institute of General Surgery, Jinling Hospital, School of Medicine Southeast University Nanjing ChinaAbstract Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT‐29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL‐mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro‐necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA‐induced intestinal injury and sepsis. Conclusions These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING‐driven inflammatory diseases.https://doi.org/10.1002/ctm2.1334inflammationMLKLRIPK3sepsisSTING |
| spellingShingle | Xufei Zhang Jie Wu Qinjie Liu Xuanheng Li Yiyu Yang Lei Wu Xiuwen Wu Yun Zhao Jianan Ren RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis Clinical and Translational Medicine inflammation MLKL RIPK3 sepsis STING |
| title | RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis |
| title_full | RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis |
| title_fullStr | RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis |
| title_full_unstemmed | RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis |
| title_short | RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis |
| title_sort | ripk3 mlkl necroptotic signalling amplifies sting pathway and exacerbates lethal sepsis |
| topic | inflammation MLKL RIPK3 sepsis STING |
| url | https://doi.org/10.1002/ctm2.1334 |
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