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

Nathalie Cadieux,Sheldon L. Morris,Michael J. Brennan,Hannah Cohen,Dragan Maric,Marcela Parra

doi:10.1099/mic.0.041996-0

Nathalie Cadieux, Sheldon L. Morris + Show 4 more

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https://doi.org/10.1099/mic.0.041996-0

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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.

Highlights

One third of the world’s population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis
One molecule that has been implicated in M. tuberculosis pathogenesis is the PE_PGRS33 protein (Brennan et al, 2001; Balaji et al, 2007)
We have investigated the localization of the M. tuberculosis PE_PGRS33 protein in transfected eukaryotic cells and have demonstrated that it co-localized to the mitochondria

Summary

Introduction

One third of the world’s population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. The exact roles of the PE_PGRS proteins in M. tuberculosis biology and pathogenesis have not been clearly elucidated, previous studies have shown that they are surface-exposed and available for interactions with the host (Delogu et al, 2004), differentially expressed during growth and infection (Delogu et al, 2006; Dheenadhayalan et al, 2006b; Espitia et al, 1999; Flores & Espitia, 2003; Ramakrishnan et al, 2000; Talaat et al, 2004) and involved in creating antigenic variability (Karboul et al, 2008; Talarico et al, 2005, 2007, 2008)

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