Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity

Abstract

SummaryThe pe/ppe genes represent one of the most intriguing aspects of the Mycobacterium tuberculosis genome. These genes are especially abundant in pathogenic mycobacteria, with more than 160 members in M. tuberculosis. Despite being discovered over 15 years ago, their function remains unclear, although various lines of evidence implicate selected family members in mycobacterial virulence. In this review, we use PE/PPE phylogeny as a framework within which we examine the diversity and putative functions of these proteins. We report on the evolution and diversity of the respective gene families, as well as the implications thereof for function and host immune recognition. We summarize recent findings on pe/ppe gene regulation, also placing this in the context of PE/PPE phylogeny. We collate data from several large proteomics datasets, providing an overview of PE/PPE localization, and discuss the implications this may have for host responses. Assessment of the current knowledge of PE/PPE diversity suggests that these proteins are not variable antigens as has been so widely speculated; however, they do clearly play important roles in virulence. Viewing the growing body of pe/ppe literature through the lens of phylogeny reveals trends in features and function that may be associated with the evolution of mycobacterial pathogenicity.

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

“…The pe and ppe genes are differentially regulated at the transcriptional level in response to a variety of environmental signals (29) and are frequently found among the differentially expressed genes in regulatory mutants (30,31). In addition, there is evidence that some PE_PGRS family members are expressed specifically in granulomatous lesions (32).…”

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

“…Unlike other PE-PPE proteins located in a row in the ESX region (20), MTBK_24820 exists independently, without PE proteins in the insertion region. MTBK_24820 is a PPE-MTPR subfamily with repeats of NxGxGNxG in the C terminus (17,21) and is orthologous to the M. tuberculosis H37Rv PPE39 protein (annotated Rv2353c) (22). PPE39 has a number of highly genetic variables among several M. tuberculosis isolates, caused by IS6110 integration and the addition of single-nucleotide polymorphisms (SNPs) (23).…”

Mycobacterium tuberculosis PPE25 and PPE26 proteins expressed in Mycobacterium smegmatis modulate cytokine secretion in mouse macrophages and enhance mycobacterial survival

“…PE and PPE family proteins, characterized by conserved Nterminal proline-glutamate (PE) and proline-proline-glutamate (PPE) motifs, are unique to mycobacteria [18]. There are 99 PE proteins and 69 PPE proteins in the M. tuberculosis H37Rv strain, and they represent about 10% of the total coding capacity of the M. tuberculosis genome [9].…”

“…PE/PPE family proteins are mainly presented in pathogenic mycobacteria species and they are usually expressed during infection and secreted or exposed to the cell surface. All these factors imply that PE/PPE proteins play a critical role in mycobacterial pathogenicity [32,1,18]. Although the functions of these proteins are not fully understood, recent studies indicate that they were associated with antigenic diversity, hostepathogen interactions and immune evasion [2,20].…”