ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses
The ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with fork head-associated domain)-TRAF6 signaling pathway plays a pivotal role in regulating inflammatory processes, with TIFA and TRAF6 serving as key molecules in this cascade. Despite its significance, the functional mechanism of TIFA-TRAF...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science
2024-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0315 |
| _version_ | 1797310984169193472 |
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| author | Liping Li Jia Wang Xincheng Zhong Yaoyao Jiang Gaofeng Pei Xikang Yang Kaixiang Zhang Siqi Shen Xue Jin Gaoge Sun Chaofei Su Shuzhen Chen Hang Yin |
| author_facet | Liping Li Jia Wang Xincheng Zhong Yaoyao Jiang Gaofeng Pei Xikang Yang Kaixiang Zhang Siqi Shen Xue Jin Gaoge Sun Chaofei Su Shuzhen Chen Hang Yin |
| author_sort | Liping Li |
| collection | DOAJ |
| description | The ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with fork head-associated domain)-TRAF6 signaling pathway plays a pivotal role in regulating inflammatory processes, with TIFA and TRAF6 serving as key molecules in this cascade. Despite its significance, the functional mechanism of TIFA-TRAF6 remains incompletely understood. In this study, we unveil that TIFA undergoes liquid–liquid phase separation (LLPS) induced by ALPK1 in response to adenosine diphosphate (ADP)-β-D-manno-heptose (ADP-Hep) recognition. The phase separation of TIFA is primarily driven by ALPK1, the pT9-FHA domain, and the intrinsically disordered region segment. Simultaneously, TRAF6 exhibits phase separation during ADP-Hep-induced inflammation, a phenomenon observed consistently across various inflammatory signal pathways. Moreover, TRAF6 is recruited within the TIFA condensates, facilitating lysine (K) 63-linked polyubiquitin chain synthesis. The subsequent recruitment, enrichment, and activation of downstream effectors within these condensates contribute to robust inflammatory signal transduction. Utilizing a novel chemical probe (compound 22), our analysis demonstrates that the activation of the ALPK1-TIFA-TRAF6 signaling pathway in response to small molecules necessitates the phase separation of TIFA. In summary, our findings reveal TIFA as a sensor for upstream signals, initiating the LLPS of itself and downstream proteins. This process results in the formation of membraneless condensates within the ALPK1-TIFA-TRAF6 pathway, suggesting potential applications in therapeutic biotechnology development. |
| first_indexed | 2024-03-08T01:51:57Z |
| format | Article |
| id | doaj.art-660b604bde894724bc87d5896b2b0e8d |
| institution | Directory Open Access Journal |
| issn | 2639-5274 |
| language | English |
| last_indexed | 2024-03-08T01:51:57Z |
| publishDate | 2024-01-01 |
| publisher | American Association for the Advancement of Science |
| record_format | Article |
| series | Research |
| spelling | doaj.art-660b604bde894724bc87d5896b2b0e8d2024-02-14T09:31:08ZengAmerican Association for the Advancement of ScienceResearch2639-52742024-01-01710.34133/research.0315ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune ResponsesLiping Li0Jia Wang1Xincheng Zhong2Yaoyao Jiang3Gaofeng Pei4Xikang Yang5Kaixiang Zhang6Siqi Shen7Xue Jin8Gaoge Sun9Chaofei Su10Shuzhen Chen11Hang Yin12State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Institute for Precision Medicine, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.The ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with fork head-associated domain)-TRAF6 signaling pathway plays a pivotal role in regulating inflammatory processes, with TIFA and TRAF6 serving as key molecules in this cascade. Despite its significance, the functional mechanism of TIFA-TRAF6 remains incompletely understood. In this study, we unveil that TIFA undergoes liquid–liquid phase separation (LLPS) induced by ALPK1 in response to adenosine diphosphate (ADP)-β-D-manno-heptose (ADP-Hep) recognition. The phase separation of TIFA is primarily driven by ALPK1, the pT9-FHA domain, and the intrinsically disordered region segment. Simultaneously, TRAF6 exhibits phase separation during ADP-Hep-induced inflammation, a phenomenon observed consistently across various inflammatory signal pathways. Moreover, TRAF6 is recruited within the TIFA condensates, facilitating lysine (K) 63-linked polyubiquitin chain synthesis. The subsequent recruitment, enrichment, and activation of downstream effectors within these condensates contribute to robust inflammatory signal transduction. Utilizing a novel chemical probe (compound 22), our analysis demonstrates that the activation of the ALPK1-TIFA-TRAF6 signaling pathway in response to small molecules necessitates the phase separation of TIFA. In summary, our findings reveal TIFA as a sensor for upstream signals, initiating the LLPS of itself and downstream proteins. This process results in the formation of membraneless condensates within the ALPK1-TIFA-TRAF6 pathway, suggesting potential applications in therapeutic biotechnology development.https://spj.science.org/doi/10.34133/research.0315 |
| spellingShingle | Liping Li Jia Wang Xincheng Zhong Yaoyao Jiang Gaofeng Pei Xikang Yang Kaixiang Zhang Siqi Shen Xue Jin Gaoge Sun Chaofei Su Shuzhen Chen Hang Yin ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses Research |
| title | ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses |
| title_full | ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses |
| title_fullStr | ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses |
| title_full_unstemmed | ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses |
| title_short | ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses |
| title_sort | adp hep induced liquid phase condensation of tifa traf6 activates alpk1 tifa dependent innate immune responses |
| url | https://spj.science.org/doi/10.34133/research.0315 |
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