Borbora, SM and Rajmani, RS and Balaji, KN (2022) PRMT5 epigenetically regulates the E3 ubiquitin ligase ITCH to influence lipid accumulation during mycobacterial infection. In: PLoS Pathogens, 18 (6).
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Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), triggers enhanced accumulation of lipids to generate foamy macrophages (FMs). This process has been often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in those involved in lipid efflux. Here, we define an Mtb-orchestrated modulation of the ubiquitination of lipid accumulation markers to enhance lipid accretion during infection. We find that Mtb infection represses the expression of the E3 ubiquitin ligase, ITCH, resulting in the sustenance of key lipid accrual molecules viz. ADRP and CD36, that are otherwise targeted by ITCH for proteasomal degradation. In line, overexpressing ITCH in Mtb-infected cells was found to suppress Mtb-induced lipid accumulation. Molecular analyses including loss-of-function and ChIP assays demonstrated a role for the concerted action of the transcription factor YY1 and the arginine methyl transferase PRMT5 in restricting the expression of Itch gene by conferring repressive symmetrical H4R3me2 marks on its promoter. Consequently, siRNA-mediated depletion of YY1 or PRMT5 rescued ITCH expression, thereby compromising the levels of Mtb-induced ADRP and CD36 and limiting FM formation during infection. Accumulation of lipids within the host has been implicated as a pro-mycobacterial process that aids in pathogen persistence and dormancy. In line, we found that perturbation of PRMT5 enzyme activity resulted in compromised lipid levels and reduced mycobacterial survival in mouse peritoneal macrophages (ex vivo) and in a therapeutic mouse model of TB infection (in vivo). These findings provide new insights into the role of PRMT5 and YY1 in augmenting mycobacterial pathogenesis. Thus, we posit that our observations could help design novel adjunct therapies and combinatorial drug regimen for effective anti-TB strategies. Copyright: © 2022 Borbora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
| Item Type: | Journal Article |
|---|---|
| Publication: | PLoS Pathogens |
| Publisher: | Public Library of Science |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | adipophilin; CD36 antigen; eosin; hematoxylin; mammalian target of rapamycin complex 1; Notch1 receptor; PRMT5 inhibitor; protein arginine methyltransferase; Protein arginine methyltransferase 5; protein inhibitor; small interfering RNA; transcription factor YY1; ubiquitin protein ligase E3; unclassified drug; lipid; ubiquitin protein ligase, animal cell; animal experiment; animal model; animal tissue; Article; bacterial load; bacterial survival; bioinformatics; chromatin immunoprecipitation; colony forming unit; confocal microscopy; controlled study; down regulation; epigenetics; gene expression; genetic transfection; immunoblotting; immunofluorescence; immunofluorescence microscopy; lipid homeostasis; lipid level; lipid storage; methylation; Mycobacterium tuberculosis; nonhuman; Notch signaling; peritoneum macrophage; protein expression; RAW 264.7 cell line; real time polymerase chain reaction; RNA isolation; tuberculosis; ubiquitination; Western blotting; animal; genetics; metabolism; mouse; Mycobacterium tuberculosis; tuberculosis, Animals; Lipids; Mice; Mycobacterium tuberculosis; Tuberculosis; Ubiquitin-Protein Ligases; Ubiquitination |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research |
| Date Deposited: | 24 Sep 2022 03:15 |
| Last Modified: | 24 Sep 2022 03:15 |
| URI: | https://eprints.iisc.ac.in/id/eprint/76633 |
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