Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.
Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.
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DOI：
10.1002/anie.202109464
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发表时间：
2021-12-06
期刊：
影响因子：
--
通讯作者：
Luo C
中科院分区：
文献类型：
--
作者：
Fan S;Yue L;Wan W;Zhang Y;Zhang B;Otomo C;Li Q;Lin T;Hu J;Xu P;Zhu M;Tao H;Chen Z;Li L;Ding H;Yao Z;Lu J;Wen Y;Zhang N;Tan M;Chen K;Xie Y;Otomo T;Zhou B;Jiang H;Dang Y;Luo C
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 the interface. Through screening covalent compounds, we discover 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. Through screening on covalent probe library, we discovered small molecule DC-LC3in covalently targeting LC3A/B on the Lys49 which could be modificated by acetylation. After crystal sturcture evaluation and further optimization, a more potent probe DC-LC3in-D5 was discovered and showed high selectivity to LC3A/B among proteome. DC-LC3in-D5 could inhibit autophagy by attenuating LC3B lipidation, which subsequently reduces the extent of autophagic structure formation and later substrate degradation.
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