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PRMT5 epigenetically regulates the E3 ubiquitin ligase ITCH to influence lipid accumulation during mycobacterial infection.
Borbora, Salik Miskat; Rajmani, Raju S; Balaji, Kithiganahalli Narayanaswamy.
  • Borbora SM; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
  • Rajmani RS; Center for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India.
  • Balaji KN; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
PLoS Pathog ; 18(6): e1010095, 2022 06.
Article in English | MEDLINE | ID: covidwho-1951565
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Tuberculosis / Mycobacterium tuberculosis Type of study: Observational study / Prognostic study Limits: Animals Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010095

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Tuberculosis / Mycobacterium tuberculosis Type of study: Observational study / Prognostic study Limits: Animals Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010095