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PROTAC-Mediated HDAC7 Protein Degradation Unveils Its Deacetylase-Independent Proinflammatory Function in Macrophages.

التفاصيل البيبلوغرافية
العنوان: PROTAC-Mediated HDAC7 Protein Degradation Unveils Its Deacetylase-Independent Proinflammatory Function in Macrophages.
المؤلفون: Kadier K; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Niu T; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Ding B; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Chen B; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Qi X; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Chen D; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Cheng X; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Fang Y; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Zhou J; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Zhao W; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China., Liu Z; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Yuan Y; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Zhou Z; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China., Dong X; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, P. R. China.; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Cancer Center, Zhejiang University, Hangzhou, 310058, P. R. China., Yang B; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, P. R. China.; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Cancer Center, Zhejiang University, Hangzhou, 310058, P. R. China.; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310058, P. R. China.; School of Medicine, Hangzhou City University, Hangzhou, 310015, P. R. China., He Q; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, P. R. China.; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Cancer Center, Zhejiang University, Hangzhou, 310058, P. R. China.; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310058, P. R. China.; Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, 310058, P. R. China., Cao J; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, P. R. China.; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Cancer Center, Zhejiang University, Hangzhou, 310058, P. R. China.; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310058, P. R. China., Jiang L; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China., Zhu CL; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, P. R. China.; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310018, P. R. China.; Cancer Center, Zhejiang University, Hangzhou, 310058, P. R. China.; Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, 310058, P. R. China.
المصدر: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Sep; Vol. 11 (36), pp. e2309459. Date of Electronic Publication: 2024 Jul 25.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Weinheim : WILEY-VCH, [2014]-
مواضيع طبية MeSH: Macrophages*/metabolism , Macrophages*/drug effects , Histone Deacetylases*/metabolism , Inflammation*/metabolism , Inflammation*/drug therapy, Animals ; Mice ; Signal Transduction/drug effects ; Lipopolysaccharides/pharmacology ; Disease Models, Animal ; Mice, Inbred C57BL ; Proteolysis/drug effects ; Toll-Like Receptor 4/metabolism
مستخلص: Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan-inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC-based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)-stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll-like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor-associated factor 6 and TGFβ-activated kinase 1 (TRAF6-TAK1) complex, thereby initiating the activation of the downstream mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti-inflammatory treatments.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
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معلومات مُعتمدة: 82373712 National Natural Science Foundation of China; 226-2023-00059 Fundamental Research Funds for the Central Universities; 2023M733126 China Postdoctoral Science Foundation; LR22H310002 Natural Science Foundation of Zhejiang Province
فهرسة مساهمة: Keywords: HDAC7; PROTAC; TLR4 signaling; anti‐inflammatory drug development; proinflammatory cytokines
المشرفين على المادة: EC 3.5.1.98 (Histone Deacetylases)
0 (Lipopolysaccharides)
EC 3.5.1.98 (Hdac7 protein, mouse)
0 (Toll-Like Receptor 4)
تواريخ الأحداث: Date Created: 20240725 Date Completed: 20240925 Latest Revision: 20240927
رمز التحديث: 20240927
مُعرف محوري في PubMed: PMC11423193
DOI: 10.1002/advs.202309459
PMID: 39049738
قاعدة البيانات: MEDLINE
الوصف
تدمد:2198-3844
DOI:10.1002/advs.202309459