Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein

Microbiology (Reading). 2011 Mar;157(Pt 3):793-804. doi: 10.1099/mic.0.041996-0. Epub 2010 Nov 16.

Abstract

PE_PGRS33 is the most studied member of the unique PE family of mycobacterial proteins. These proteins are composed of a PE domain (Pro-Glu motif), a linker region and a PGRS domain (polymorphic GC-rich-repetitive sequence). Previous studies have shown that PE_PGRS33 is surface-exposed, constitutively expressed during growth and infection, involved in creating antigenic diversity, and able to induce death in transfected or infected eukaryotic cells. In this study, we showed that PE_PGRS33 co-localizes to the mitochondria of transfected cells, a phenomenon dependent on the linker region and the PGRS domain, but not the PE domain. Using different genetic fusions and chimeras, we also demonstrated a direct correlation between localization to the host mitochondria and the induction of cell death. Finally, although all constructs localizing to the mitochondria did induce apoptosis, only the wild-type PE_PGRS33 with its own PE domain also induced primary necrosis, indicating a potentially important role for the PE domain. Considering the importance of primary necrosis in Mycobacterium tuberculosis dissemination during natural infection, the PE_PGRS33 protein may play a crucial role in the pathogenesis of tuberculosis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, Bacterial / metabolism*
  • Apoptosis
  • Bacterial Proteins / metabolism*
  • Cell Death*
  • Cell Line, Tumor
  • Fluorescent Dyes / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mycobacterium tuberculosis / metabolism
  • Mycobacterium tuberculosis / pathogenicity*
  • Necrosis
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Fluorescent Dyes
  • Membrane Proteins
  • PE-PGRS protein, Mycobacterium
  • Recombinant Fusion Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins