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

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)....

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Published in:Autophagy 2022-12, Vol.18 (12), p.2926-2945
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Apoptosis Regulatory Proteins - metabolism
Autophagy - genetics
BCG Vaccine
Cytokines - metabolism
Inflammation
lysosomal degradation
Macroautophagy
Mice
Mycobacterium tuberculosis
N-degron pathway
Research Paper
Salmonella typhimurium - metabolism
selective autophagy
Sequestosome-1 Protein - metabolism
Sirolimus - pharmacology
Ubiquitin - metabolism
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Summary: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-Guérin (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. Abbreviations: ATG: autophagy-related gene; BCG: Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent protein; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1: Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; UBA: ubiquitin-associated.
ISSN:1554-8627
1554-8635
DOI:10.1080/15548627.2022.2054240