Acetylation is required for full activation of the NLRP3 inflammasome
Abstract Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44203-0 |
| _version_ | 1797376940267536384 |
|---|---|
| author | Yening Zhang Ling Luo Xueming Xu Jianfeng Wu Fupeng Wang Yanyan Lu Ningjie Zhang Yingying Ding Ben Lu Kai Zhao |
| author_facet | Yening Zhang Ling Luo Xueming Xu Jianfeng Wu Fupeng Wang Yanyan Lu Ningjie Zhang Yingying Ding Ben Lu Kai Zhao |
| author_sort | Yening Zhang |
| collection | DOAJ |
| description | Abstract Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs induced by the second signal are less well characterized. Here, we show that the assembly signal involves acetylation of NLRP3 at lysine 24, which is important for the oligomerization and the actual assembly of NLRP3 without affecting its recruitment to dispersed trans-Golgi network (dTGN). Accordingly, NLRP3 inflammasome activation is impaired in NLRP3-K24R knock-in mice. We identify KAT5 as an acetyltransferase able to acetylate NLRP3. KAT5 deficiency in myeloid cells and pharmacological inhibition of KAT5 enzymatic activity reduce activation of the NLRP3 inflammasome, both in vitro and in vivo. Thus, our study reveals a key mechanism for the oligomerization and full activation of NLRP3 and lays down the proof of principle for therapeutic targeting of the KAT5-NLRP3 axis. |
| first_indexed | 2024-03-08T19:45:51Z |
| format | Article |
| id | doaj.art-d40e729192aa44b5b3bf016771f1326a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T19:45:51Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d40e729192aa44b5b3bf016771f1326a2023-12-24T12:24:06ZengNature PortfolioNature Communications2041-17232023-12-0114111210.1038/s41467-023-44203-0Acetylation is required for full activation of the NLRP3 inflammasomeYening Zhang0Ling Luo1Xueming Xu2Jianfeng Wu3Fupeng Wang4Yanyan Lu5Ningjie Zhang6Yingying Ding7Ben Lu8Kai Zhao9Department of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityState Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityDepartment of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityDepartment of Hematology, The Second Xiangya Hospital, Central South UniversityDepartment of Blood Transfusion, The Second Xiangya Hospital, Central South UniversityDepartment of Pathogen Biology, NavaMedical UniversityDepartment of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, the Third Xiangya Hospital, Central South UniversityAbstract Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs induced by the second signal are less well characterized. Here, we show that the assembly signal involves acetylation of NLRP3 at lysine 24, which is important for the oligomerization and the actual assembly of NLRP3 without affecting its recruitment to dispersed trans-Golgi network (dTGN). Accordingly, NLRP3 inflammasome activation is impaired in NLRP3-K24R knock-in mice. We identify KAT5 as an acetyltransferase able to acetylate NLRP3. KAT5 deficiency in myeloid cells and pharmacological inhibition of KAT5 enzymatic activity reduce activation of the NLRP3 inflammasome, both in vitro and in vivo. Thus, our study reveals a key mechanism for the oligomerization and full activation of NLRP3 and lays down the proof of principle for therapeutic targeting of the KAT5-NLRP3 axis.https://doi.org/10.1038/s41467-023-44203-0 |
| spellingShingle | Yening Zhang Ling Luo Xueming Xu Jianfeng Wu Fupeng Wang Yanyan Lu Ningjie Zhang Yingying Ding Ben Lu Kai Zhao Acetylation is required for full activation of the NLRP3 inflammasome Nature Communications |
| title | Acetylation is required for full activation of the NLRP3 inflammasome |
| title_full | Acetylation is required for full activation of the NLRP3 inflammasome |
| title_fullStr | Acetylation is required for full activation of the NLRP3 inflammasome |
| title_full_unstemmed | Acetylation is required for full activation of the NLRP3 inflammasome |
| title_short | Acetylation is required for full activation of the NLRP3 inflammasome |
| title_sort | acetylation is required for full activation of the nlrp3 inflammasome |
| url | https://doi.org/10.1038/s41467-023-44203-0 |
| work_keys_str_mv | AT yeningzhang acetylationisrequiredforfullactivationofthenlrp3inflammasome AT lingluo acetylationisrequiredforfullactivationofthenlrp3inflammasome AT xuemingxu acetylationisrequiredforfullactivationofthenlrp3inflammasome AT jianfengwu acetylationisrequiredforfullactivationofthenlrp3inflammasome AT fupengwang acetylationisrequiredforfullactivationofthenlrp3inflammasome AT yanyanlu acetylationisrequiredforfullactivationofthenlrp3inflammasome AT ningjiezhang acetylationisrequiredforfullactivationofthenlrp3inflammasome AT yingyingding acetylationisrequiredforfullactivationofthenlrp3inflammasome AT benlu acetylationisrequiredforfullactivationofthenlrp3inflammasome AT kaizhao acetylationisrequiredforfullactivationofthenlrp3inflammasome |