Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein

doi:10.1002/anie.202109464

	Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein
	Fan, Shijie 1,2; Yue, Liyan 1; Wan, Wei 1,2; Zhang, Yuanyuan 1,2; Zhang, Bidong 1; Otomo, Chinatsu 3; Li, Quanfu 4; Lin, Tingting 1,5; Hu, Junchi 6; Xu, Pan 1
刊名	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
	2021-11-05
页码	11
关键词	covalent modification probes proteome LC3 post-translational modification
ISSN号	1433-7851
DOI	10.1002/anie.202109464
通讯作者	Zhou, Bing(zhoubing@simm.ac.cn) ; Jiang, Hualiang(hljiang@simm.ac.cn) ; Dang, Yongjun(yongjundang@fudan.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	The autophagic ubiquitin-like protein LC3 functions through interactions with LC3-interaction regions (LIRs) of other autophagy proteins, including autophagy receptors, which stands out as a promising protein-protein interaction (PPI) target for the intervention of autophagy. Post-translational modifications like acetylation of Lys49 on the LIR-interacting surface could disrupt the interaction, offering an opportunity to design covalent small molecules interfering with the interface. Through screening covalent compounds, we discovered a small molecule modulator of LC3A/B that covalently modifies LC3A/B protein at Lys49. Activity-based protein profiling (ABPP) based evaluations reveal that a derivative molecule DC-LC3in-D5 exhibits a potent covalent reactivity and selectivity to LC3A/B in HeLa cells. DC-LC3in-D5 compromises LC3B lipidation in vitro and in HeLa cells, leading to deficiency in the formation of autophagic structures and autophagic substrate degradation. DC-LC3in-D5 could serve as a powerful tool for autophagy research as well as for therapeutic interventions.
资助项目	National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[31270830] ; National Natural Science Foundation of China[21572038] ; National Natural Science Foundation of China[22137002] ; Chinese Academy of Science[CASIMM0120184015] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; National Institutes of Health[GM092740]
WOS关键词	STRUCTURAL BASIS ; POSTTRANSLATIONAL MODIFICATION ; ATG8 ; CONTRIBUTES ; SUPPRESSION ; LIPIDATION ; MECHANISMS ; CONJUGATE ; IMMUNITY ; FAMILY
WOS研究方向	Chemistry
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000714779000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298765]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Bing; Jiang, Hualiang; Dang, Yongjun; Luo, Cheng
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA 4.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 6.Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Inst Life Sci, 1 Yixueyuan Rd, Chongqing, Peoples R China 7.Suzhou Autopharm, 108 Yuxin Rd, Suzhou 215123, Jiangsu, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 9.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 10.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China
推荐引用方式 GB/T 7714	Fan, Shijie,Yue, Liyan,Wan, Wei,et al. Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2021:11.
APA	Fan, Shijie.,Yue, Liyan.,Wan, Wei.,Zhang, Yuanyuan.,Zhang, Bidong.,...&Luo, Cheng.(2021).Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,11.
MLA	Fan, Shijie,et al."Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021):11.