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Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria

Cited 19 time in Web of Science Cited 19 time in Scopus

Lee, Yoon Jee; Kim, Jin Kyung; Jung, Chan Hoon; Kim, Young Jae; Jung, Eui Jung; Lee, Su Hyun; Choi, Ha Rim; Son, Yeon Sung; Shim, Sang Mi; Jeon, Sang Min; Choe, Jin Ho; Lee, Sang-Hee; Whang, Jake; Sohn, Kyung-Cheol; Hur, Gang Min; Kim, Hyun Tae; Yeom, Jinki; Jo, Eun-Kyeong; Kwon, Yong Tae

Issue Date
Landes Bioscience
Autophagy, Vol.18 No.12, pp.2926-2945
The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1), these chemicals induced the biogenesis and recruitment of autophagic membranes to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The antimicrobial efficacy was independent of rapamycin-modulated core autophagic pathways and synergistic with the reduced production of inflammatory cytokines. In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium, Bacillus Calmette-Guerin (BCG), and Mtb as well as multidrug-resistant Mtb and inhibited the production of inflammatory cytokines. This dual mode of action in xenophagy and inflammation significantly protected mice from inflammatory lesions in the lungs and other tissues caused by all the tested bacterial strains. Our results suggest that the N-degron pathway provides a therapeutic target in host-directed therapeutics for a broad range of drug-resistant intracellular pathogens.
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  • College of Pharmacy
  • Department of Pharmacy
Research Area Cancer Origin, Metabolism, Toxicology


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