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PE_PGRS38 Interaction With HAUSP Downregulates Antimycobacterial Host Defense via TRAF6

Jae-Sung Kim1,2, Hyo Keun Kim3,4, Euni Cho1,4

  • 1Department of Bionano Technology, Hanyang University, Seoul, South Korea.

Frontiers in Immunology
|May 16, 2022
PubMed

Insights

Mycobacterium tuberculosis (Mtb) protein PE_PGRS38 interacts with HAUSP to regulate host immunity. This interaction inhibits deubiquitination of TRAF6, increasing Mtb survival and bacterial burden.

Area of Science:

  • Immunology
  • Microbiology
  • Molecular Biology

Background:

  • Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) by manipulating host immunity.
  • The PE_PGRS protein family is crucial for Mtb pathogenesis.
  • Understanding PE_PGRS functions is key to deciphering TB pathogenesis.

Purpose of the Study:

  • Investigate the role of PE_PGRS38 in Mtb pathogenesis.
  • Elucidate the interaction between PE_PGRS38 and herpesvirus-associated ubiquitin-specific protease (HAUSP, USP7).
  • Determine how this interaction affects host immune responses and bacterial survival.

Main Methods:

  • Constructed recombinant PE_PGRS38 expressed in Mycobacterium smegmatis (Ms_PE_PGRS38).
  • Assessed the effect of Ms_PE_PGRS38 on cytokine levels in murine bone marrow-derived macrophages.
  • Investigated the deubiquitination of tumor necrosis factor receptor-associated factor (TRAF) 6 by HAUSP.
  • Identified the essential domain of PE_PGRS38 for mediating TRAF6 deubiquitination.

Main Results:

  • Ms_PE_PGRS38 inhibited HAUSP-mediated deubiquitination of TRAF6.
  • The PE domain of PE_PGRS38 is essential for TRAF6 deubiquitination.
  • Ms_PE_PGRS38 modulated cytokine levels, leading to increased intracellular bacterial burden in vitro and in vivo.

Conclusions:

  • The interaction between HAUSP and PE_PGRS38 regulates the host inflammatory response.
  • This interplay enhances mycobacterial survival and colonization.
  • PE_PGRS38 is a significant virulence factor in Mtb pathogenesis.
Keywords:
HAUSPMacrophagesMycobacterium smegmatisMycobacterium tuberculosis PE_PGRS38TRAF6Ubiquitination

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