Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria
Creators: name: Lee, Yoon Jee
name: Kim, Jin Kyung
name: Jung, Chan Hoon
name: Kim, Young Jae
name: Jung, Eui Jung
name: Lee, Su Hyun
name: Choi, Ha Rim
name: Son, Yeon Sung
name: Shim, Sang Mi
name: Jeon, Sang Min
name: Choe, Jin Ho
name: Lee, Sang-Hee
name: Whang, Jake
name: Sohn, Kyung-Cheol
name: Hur, Gang Min
name: Kim, Hyun Tae
name: Yeom, Jinki
name: Jo, Eun-Kyeong
name: Kwon, Yong Tae
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biophysics
subject: Biochemistry
subject: Space Science
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: 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 <i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>. Typhimurium), <i>Escherichia coli</i>, and <i>Streptococcus pyogenes</i> as well as <i>Mycobacterium tuberculosis</i> (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 <i>S</i>. 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. <b>Abbreviations</b>: 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: <i>Mycobacterium tuberculosis</i>; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1: Phox and Bem1; SQSTM1/p62: sequestosome 1; <i>S</i>. Typhimurium: <i>Salmonella enterica</i> serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; UBA: ubiquitin-associated.