An immunomodulatory role for the <i><scp>M</scp>ycobacterium tuberculosis</i> region of difference 1 locus proteins <scp>PE</scp>35 (<scp>R</scp>v3872) and <scp>PPE</scp>68 (<scp>R</scp>v3873)

Tiwari, Bhavana; Soory, Amarendranath; Raghunand, Tirumalai R.

doi:10.1111/febs.12723

Cited by 53 publications

(59 citation statements)

References 63 publications

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“…Akin to our study on PPE18, recent reports now show a similar role of other PE/PPE proteins as well as ESAT-6 in subverting the normal macrophage innate immune response, by inhibiting the macrophage inflammatory responses by TLR2 signaling (Deng et al, 2014;Pathak et al, 2007;Tiwari et al, 2014;Tiwari et al, 2012), surmising that pe/ppe genes being in close proximity with esat-6 like genes constitute the pathogens effort during evolution to cluster together and then induce effectors important for virulence and pathogenesis of M. tuberculosis. Because of their importance in detection and containment of mycobacterium, pathogenic mycobacterium may target TLR2 signaling as a mode of immune evasion.…”

Section: Hijacking Of Tlr2 and Th1-th2 Differentiation By Mycobacterisupporting

confidence: 64%

“…However, induction of pro-inflammatory cytokines such as TNF-α by Mtbhsp60 required its sequestration to the membrane either through TLR2 or TLR4, resulting in activation of ERK1/2 signaling cascades (Parveen et al, 2013). Similarly PPE32, PE5-PE4 and PE15-PPE20 and PE35 and PPE68 were also shown to manipulate the host cytokine, via alterationof the MAPK signaling pathways (Tiwari et al, 2014;Tiwari et al, 2012). Thus, the capacity for distinct M.tb agonists to dictate these MAPK signaling cascades downstream of TLR2 could provide an additional means for the bacilli to modulate macrophage-effector responses.…”

Section: Hijacking Of Tlr2 and Th1-th2 Differentiation By Mycobacterimentioning

confidence: 94%

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Immunomodulatory Role of Mycobacterial PE/PPE Family of Proteins

Nair¹

2014

Proceedings of the Indian National Science Academy

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Mycobacterium tuberculosis (M.tb) is an adept pathogen possessing unique strategies to exploit and corrupt the very core defense systems designed to curb its own survival and multiplication. Comparative analysis of mycobacterial genomes indicate that the pathogenic mycobacterium have acquired a multitude of genes which play important roles in modulating protective host-cell signaling that are triggered in response to an infection. Therefore, defining the "set of genes" expressed by intracellular pathogens as well as understanding modulations of host-signaling pathways during infection is extremely crucial to devise successful clinical intervention against the development of disease. The unique PE/PPE proteins, which constitute about 10% of coding capacity of M.tb genome, owing to their high abundance and expansion in pathogenic mycobacterial species warrants a better understanding of their role in mycobacterial pathogenesis. The PE/PPE families have been thought to play important roles in generating antigenic variation and immune evasion. Although a comprehensive understanding of their role is yet to be fully understood, emerging evidence supports a role of PE/PPE proteins at multiple levels of infectious process. This review delineates the importance of these proteins in the modulation of macrophage immune effector responses, as well as importance of these proteins in clinical manifestations of TB.

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Section: Hijacking Of Tlr2 and Th1-th2 Differentiation By Mycobacterisupporting

confidence: 64%

Section: Hijacking Of Tlr2 and Th1-th2 Differentiation By Mycobacterimentioning

confidence: 94%

Immunomodulatory Role of Mycobacterial PE/PPE Family of Proteins

Nair¹

2014

Proceedings of the Indian National Science Academy

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“…Assaying PPE-EspG binding is complicated by the fact that PPE proteins are predicted to interact with specific PE partners and function as obligate heterodimers (33); yet, aside from PE25-PPE41, very few pairs of interacting PE and PPE proteins have been identified (10,34). Indeed, recombinant expression of PPE proteins alone typically yields nonnative, aggregated, or insoluble material (10).…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%

Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

Ekiert

Cox

2014

Proc. Natl. Acad. Sci. U.S.A.

102

131

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Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways.tuberculosis | protein secretion | antigenic variation | virulence factor | host-pathogen interactions

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“…The comparative analyses of M. tuberculosis genome has shown the presence of several regions of difference (RD) between M. tuberculosis and other mycobacteria, predominantly when compared with the vaccine strains of M. bovis BCG [6]. Among these regions, RD1 appears to be important region for Type 1 T helper (Th1)-cell stimulation [7].…”

Section: Introductionmentioning

confidence: 99%

“…There are nine genes in the RD1 locus that have been shown to be necessary for the functioning of the ESAT-6 secretion system-1 secretion system (ESX-1) [6]. Two members of the PE-PPE family of proteins, namely PE35 (Rv3872) and PPE68 (Rv3873), are present within this locus [8].…”

Section: Introductionmentioning

confidence: 99%