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Proline-proline-glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter.

ABSTRACT: Cells of the monocyte/macrophage lineage are shown to play a role in the pathogenesis of human immunodeficiency virus (HIV). The occurrence of HIV type 1 (HIV-1) infection is found to be accelerated in people infected with Mycobacterium tuberculosis, but the mechanism by which mycobacterial protein(s) induces HIV-1 LTR trans-activation is not clearly understood. We show here that the M. tuberculosis proline-proline-glutamic acid (PPE) protein Rv1168c (PPE17) can augment transcription from HIV-1 LTR in monocyte/macrophage cells. Rv1168c interacts specifically with Toll-like receptor-2 (TLR2) resulting in downstream activation of nuclear factor-?B (NF-?B) resulting in HIV-1 LTR trans-activation. Another PPE protein, Rv1196 (PPE18), was also found to interact with TLR2 but had no effect on HIV-1 LTR trans-activation because of its inability to activate the NF-?B signaling pathway. In silico docking analyses and mutation experiments have revealed that the N-terminal domain of Rv1168c specifically interacts with LRR motifs 15-20 of TLR2, and this site of interaction is different from that of Rv1196 protein (LRR motifs 11-15), indicating that the site of interaction on TLR2 dictates the downstream signaling events leading to activation of NF-?B. This information may help in understanding the mechanism of pathogenesis of HIV-1 during M. tuberculosis co-infection.

SUBMITTER: Bhat KH

PROVIDER: S-EPMC3351301 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Proline-proline-glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter.

Bhat Khalid Hussain KH Chaitanya Chinta Krishna CK Parveen Nazia N Varman Raja R Ghosh Sudip S Mukhopadhyay Sangita S

The Journal of biological chemistry 20120315 20

Cells of the monocyte/macrophage lineage are shown to play a role in the pathogenesis of human immunodeficiency virus (HIV). The occurrence of HIV type 1 (HIV-1) infection is found to be accelerated in people infected with Mycobacterium tuberculosis, but the mechanism by which mycobacterial protein(s) induces HIV-1 LTR trans-activation is not clearly understood. We show here that the M. tuberculosis proline-proline-glutamic acid (PPE) protein Rv1168c (PPE17) can augment transcription from HIV-1 ...[more]

PMID: 22427668

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Project description:Iron is essential for replication of Mycobacterium tuberculosis, but iron is efficiently sequestered in the human host during infection. Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is well studied in other bacterial pathogens, little is known in M. tuberculosis To identify proteins involved in heme utilization by M. tuberculosis, a transposon mutant library was screened for resistance to the toxic heme analog gallium(III)-porphyrin (Ga-PIX). Inactivation of the ppe36, ppe62, and rv0265c genes resulted in resistance to Ga-PIX. Growth experiments using isogenic M. tuberculosis deletion mutants showed that PPE36 is essential for heme utilization by M. tuberculosis, while the functions of PPE62 and Rv0265c are partially redundant. None of the genes restored growth of the heterologous M. tuberculosis mutants, indicating that the proteins encoded by the genes have separate functions. PPE36, PPE62, and Rv0265c bind heme as shown by surface plasmon resonance spectroscopy and are associated with membranes. Both PPE36 and PPE62 proteins are cell surface accessible, while the Rv0265c protein is probably located in the periplasm. PPE36 and PPE62 are, to our knowledge, the first proline-proline-glutamate (PPE) proteins of M. tuberculosis that bind small molecules and are involved in nutrient acquisition. The absence of a virulence defect of the ppe36 deletion mutant indicates that the different iron acquisition pathways of M. tuberculosis may substitute for each other during growth and persistence in mice. The emerging model of heme utilization by M. tuberculosis as derived from this study is substantially different from those of other bacteria. IMPORTANCE:Tuberculosis is caused by Mycobacterium tuberculosis and is a devastating disease affecting eight million people each year. Iron is an essential nutrient for replication of M. tuberculosis in the human host. More than 70% of iron in the human body is bound in heme. Not surprisingly, many bacterial pathogens, including M. tuberculosis, are able to acquire iron from heme. However, the mechanism of heme uptake by M. tuberculosis is poorly understood. We have identified two novel surface proteins that bind heme and are required for heme utilization by M. tuberculosis These findings constitute a major advancement of our understanding of iron acquisition by M. tuberculosis and show that M. tuberculosis has evolved heme uptake systems different from the paradigms established by other bacteria.

Dataset Information

Proline-proline-glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter.

Publications

Proline-proline-glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter.

Similar Datasets

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