Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface

Sampson, Samantha L.

doi:10.1155/2011/497203

Cited by 229 publications

(233 citation statements)

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“…Sometimes, these N-terminal domains constitute all of the PE/PPE proteins, but they can also be fused to highly variable C-terminal domains (23). Although they are associated with mycobacterial virulence, the function of the PE and PPE proteins is largely unknown (25). Many PE and PPE proteins are exported to the bacterial cell surface or the culture supernatant (20,21,(26)(27)(28)(29).…”

mentioning

confidence: 99%

General secretion signal for the mycobacterial type VII secretion pathway

Daleke

Ummels

Bawono³

et al. 2012

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

183

224

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Mycobacterial pathogens use specialized type VII secretion (T7S) systems to transport crucial virulence factors across their unusual cell envelope into infected host cells. These virulence factors lack classical secretion signals and the mechanism of substrate recognition is not well understood. Here we demonstrate that the model T7S substrates PE25/PPE41, which form a heterodimer, are targeted to the T7S pathway ESX-5 by a signal located in the C terminus of PE25. Site-directed mutagenesis of residues within this C terminus resulted in the identification of a highly conserved motif, i.e., YxxxD/E, which is required for secretion. This motif was also essential for the secretion of LipY, another ESX-5 substrate. Pathogenic mycobacteria have several different T7S systems and we identified a PE protein that is secreted by the ESX-1 system, which allowed us to compare substrate recognition of these two T7S systems. Surprisingly, this ESX-1 substrate contained a C-terminal signal functionally equivalent to that of PE25. Exchange of these C-terminal secretion signals between the PE proteins restored secretion, but each PE protein remained secreted via its own ESX secretion system, indicating that an additional signal(s) provides system specificity. Remarkably, the YxxxD/E motif was also present in and required for efficient secretion of the ESX-1 substrates CFP-10 and EspB. Therefore, our data show that the YxxxD/E motif is a general secretion signal that is present in all known mycobacterial T7S substrates or substrate complexes.

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mentioning

confidence: 99%

General secretion signal for the mycobacterial type VII secretion pathway

Daleke

Ummels

Bawono³

et al. 2012

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

183

224

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“…The PE_PGRS (polymorphic GC-rich sequence) proteins contain multiple tandem repeats of Gly-Gly-Ala (or a variant thereof), while the PPE_MPTR (major polymorphic tandem repeat) subgroup possess polypeptides that are rich in repeats with the signature Asn-X-Gly-XGly-Asn-X-Gly. PE-PGRS and PPE_MPTR genes represent some of the most variable regions of the M.tb chromosome and consequently speculated to represent a major source of antigenic variations which has been reviewed by Sampson (Sampson, 2011). The pe and ppe genes are mostly arranged in a unique regulon with the pe genes located always upstream to the ppe genes and scattered throughout the genome (Tundup et al, 2006).…”

Section: Pe/ppe Genomicsmentioning

confidence: 99%

“…Some PE/PPEs may be actively secreted or passively shed from the bacterium into the host cell milieu, and could even be released from host cells via exosomes (Balaji et al, 2007). Thus, they are ideally positioned to interact with the host immune system and have important consequences on the outcome of infection (Sampson, 2011). Structurebased predictions based on crystal structure of PE25/ PPE41 protein pair showed considerable resemblance to the CFP-10/ESAT6 complex (Strong et al, 2006 (Voskuil et al, 2004).…”

Section: Pe/ppe Genomicsmentioning

confidence: 99%

“…Various studies suggest a role of PE/PPE proteins in subverting critical innate immune pathways by interfering with various host components (Sampson, 2011). The most widely supported theory suggests the involvement of these proteins in generation of antigenic variation due to highly polymorphic nature of their C-terminal domains (Banu et al, 2002;Delogu and Brennan, 2001).…”

Section: Diverse Functional Role Of Pe/ppe Proteinsmentioning

confidence: 99%

“…PE/PPE family members on account of being either secreted or surface exposed are known targets of humoral responses. Several PE/PPE proteins have been shown to be potent B-cell antigens and serve as sero-diagnostics markers (Sampson, 2011). Mostly, the members of PE_PGRS and PPE_MPTR families possessing highly repetitive domains are found to elicit antibody responses (Chakhaiyar et al, 2004;Delogu and Brennan, 2001;Koh et al, 2009b).…”

Section: Humoral and Cell-mediated Immune Response Against Pe/ppe Promentioning

confidence: 99%

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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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Antigenic Variation in Microbial Evasion of Immune Responses

Kotwal

Kulkarni

2013

Encyclopedia of Life Sciences

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Antigenic variation is the means by which a number of highly pathogenic microorganisms, ranging from the electronmicroscopic human viruses to bacteria to fungi and unicellular protozoan parasites, passively evade immune surveillance. Through the understanding of the growing variety of mechanisms of the antigenic variation of surface proteins, it has become possible for us to determine what is preventing the host organism from mounting an effective immune response. Antigenic variation has serious public health consequences, for example, the current human immunodeficiency virus pandemic and the looming influenza pandemic, as well as a significant challenge to developing vaccines capable of eliciting long‐lasting or life‐long protective immunity against several pathogens. Key Concepts: Antigenic variation is a major mechanism of passively evading the host immune surveillance. Antigenic variation is exhibited by a number of highly pathogenic microorganisms including human viruses, bacteria, fungi and unicellular protozoans. Antigenic variation poses challenges to vaccine development against microorganisms causing major public health problems globally. HIV‐1 surface glycoproteins display antigenic variation due to a high mutation rate during replication and significant tolerance of the variation. Heterochromatin in the chromososome ends (telomers) in the malarial parasites mediate epigenetic regulation in the malaria parasite Plasmodium falciparum . African trypanosomes control antigenic variation by periodically switching its variant surface glycoprotein involving transposition followed by recombination occurring at the telomeric expression site. Targeting conserved regions of surface glycoproteins by using broadly neutralising antibodies against highly conserved exposed sites in surface proteins. Targeting the oligosaccharides on surface glycoproteins, such as by the use of enveloped virus neutralising compounds (EVNCs).

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Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface

Cited by 229 publications

References 115 publications

General secretion signal for the mycobacterial type VII secretion pathway

General secretion signal for the mycobacterial type VII secretion pathway

Immunomodulatory Role of Mycobacterial PE/PPE Family of Proteins

Antigenic Variation in Microbial Evasion of Immune Responses

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