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.

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

“…In this study, we demonstrated that the Mtb toxin TNT damages mitochondria, a key event in the necrotic cell death of Mtb-infected macrophages (Chen et al, 2006; Duan et al, 2002; Jamwal et al, 2013). The observed mitochondrial damage is a consequence of the NAD + glycohydrolase activity of TNT and does not require a direct interaction of TNT with mitochondria, in contrast to other Mtb proteins associated with mitochondria (Cadieux et al, 2011; Sohn et al, 2011). The key observation linking NAD + depletion by TNT to necrotic cell death was that inhibition or lack of RIPK3 and/or MLKL protected Mtb-infected macrophages from TNT-induced cell death.…”

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…The ESX-5 system is crucial for the secretion of the Mtb PE/PPE family of proteins (Abdallah et al 2006(Abdallah et al , 2009. Interestingly, the PE_PGRS33 protein is transported to host cell mitochondria and induces programmed necrosis when expressed ectopically in mammalian cells (Cadieux et al 2011). It remains to be determined what the function of this protein is in the context of live Mtb infection.…”

Mycobacterial Pathogenomics and Evolution

“…The protein PE_PGRS33 (Rv1818c), for example, was described as exerting a cytotoxic effect on host cells (33,34). Interestingly, the gene encoding PE_PGRS33 in M. tuberculosis strains is not present in the genomes of Mycobacterium canettii strains, representing early branching tubercle bacilli with smooth colony morphology and showing lower virulence and persistence in animal infection models relative to M. tuberculosis (35).…”