The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation
The NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1047922/full |
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| author | Zhihao Xu Shasha Deng Yuluo Huang Yunru Yang Liangqi Sun Hanyuan Liu Dan Zhao Weihong Zeng Xueying Yin Peiyi Zheng Yingying Wang Muziying Liu Weidong Zhao Tsan Sam Xiao Ying Zhou Tengchuan Jin Tengchuan Jin Tengchuan Jin |
| author_facet | Zhihao Xu Shasha Deng Yuluo Huang Yunru Yang Liangqi Sun Hanyuan Liu Dan Zhao Weihong Zeng Xueying Yin Peiyi Zheng Yingying Wang Muziying Liu Weidong Zhao Tsan Sam Xiao Ying Zhou Tengchuan Jin Tengchuan Jin Tengchuan Jin |
| author_sort | Zhihao Xu |
| collection | DOAJ |
| description | The NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates the NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that different ASC preference in three types of inflammasomes, namely the ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that signal transduction of the NLRP1 inflammasome relies on multiple interaction surfaces at its CARD domain. Finally, our results partly explain how mutations in NLRP1 lead to its constitutive activation in auto-inflammatory diseases. In conclusion, our study not only reveals how CARD8 downregulates the NLRP1 inflammasome activation, but also provides insights into the assembly mechanisms of CARD-containing inflammasomes. |
| first_indexed | 2024-04-11T08:11:46Z |
| format | Article |
| id | doaj.art-9236b969a7c54d4a8f23ee62cde68357 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T08:11:46Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9236b969a7c54d4a8f23ee62cde683572022-12-22T04:35:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-11-011310.3389/fimmu.2022.10479221047922The CARD8 T60 variant associates with NLRP1 and negatively regulates its activationZhihao Xu0Shasha Deng1Yuluo Huang2Yunru Yang3Liangqi Sun4Hanyuan Liu5Dan Zhao6Weihong Zeng7Xueying Yin8Peiyi Zheng9Yingying Wang10Muziying Liu11Weidong Zhao12Tsan Sam Xiao13Ying Zhou14Tengchuan Jin15Tengchuan Jin16Tengchuan Jin17Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaAnhui Institute of Pediatric Research, Anhui Provincial Children’s Hospital, Hefei, ChinaDepartment of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Pathology, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaLaboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaCAS Center for Excellence in Molecular Cell Science, Chinese Academy of Science, Shanghai, ChinaThe NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates the NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that different ASC preference in three types of inflammasomes, namely the ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that signal transduction of the NLRP1 inflammasome relies on multiple interaction surfaces at its CARD domain. Finally, our results partly explain how mutations in NLRP1 lead to its constitutive activation in auto-inflammatory diseases. In conclusion, our study not only reveals how CARD8 downregulates the NLRP1 inflammasome activation, but also provides insights into the assembly mechanisms of CARD-containing inflammasomes.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1047922/fullNLRP1 inflammasomeCARD8death domain superfamilyCARDautoinflammatory diseases |
| spellingShingle | Zhihao Xu Shasha Deng Yuluo Huang Yunru Yang Liangqi Sun Hanyuan Liu Dan Zhao Weihong Zeng Xueying Yin Peiyi Zheng Yingying Wang Muziying Liu Weidong Zhao Tsan Sam Xiao Ying Zhou Tengchuan Jin Tengchuan Jin Tengchuan Jin The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation Frontiers in Immunology NLRP1 inflammasome CARD8 death domain superfamily CARD autoinflammatory diseases |
| title | The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation |
| title_full | The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation |
| title_fullStr | The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation |
| title_full_unstemmed | The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation |
| title_short | The CARD8 T60 variant associates with NLRP1 and negatively regulates its activation |
| title_sort | card8 t60 variant associates with nlrp1 and negatively regulates its activation |
| topic | NLRP1 inflammasome CARD8 death domain superfamily CARD autoinflammatory diseases |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1047922/full |
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