title: Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein.
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.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cadieux
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Parra
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cohen
authors.affiliation: National Institute of Neurological Disorders and Stroke, Flow Cytometry Core Facility, NIH, Bethesda, MD, USA.
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: Sheldon L
authors.initials: SL
authors.lastname: Morris
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brennan
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000378:metabolism / Q000472:pathogenicity*; D009336:Necrosis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D005456:Fluorescent Dyes; D008565:Membrane Proteins; C440642:PE-PGRS protein, Mycobacterium; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins