The PE-PPE Family of Mycobacterium tuberculosis: Proteins in Disguise

Abstract

Copyright © 2022 The Author(s). Mycobacterium tuberculosis has thrived in parallel with humans for millennia, and despite our efforts, M. tuberculosis continues to plague us, currently infecting a third of the world’s population. The success of M. tuberculosis has recently been attributed, in part, to the PE-PPE family; a unique collection of 168 proteins fundamentally involved in the pathogenesis of M. tuberculosis. The PE-PPE family proteins have been at the forefront of intense research efforts since their discovery in 1998 and whilst our knowledge and understanding has significantly advanced over the last two decades, many important questions remain to be elucidated.

This review consolidates and examines the vast body of existing literature regarding the PE-PPE family proteins, with respect to the latest developments in elucidating their evolution, structure, subcellular localisation, function, and immunogenicity. This review also highlights significant inconsistencies and contradictions within the field. Additionally, possible explanations for these knowledge gaps are explored. Lastly, this review poses many important questions, which need to be addressed to complete our understanding of the PE-PPE family, as well as highlighting the challenges associated with studying this enigmatic family of proteins.

Further research into the PE-PPE family, together with technological advancements in genomics and proteomics, will undoubtedly improve our understanding of the pathogenesis of M. tuberculosis, as well as identify key targets/candidates for the development of novel drugs, diagnostics, and vaccines.

Graphical abstract [available online at: https://ars.els-cdn.com/content/image/1-s2.0-S0171298522001474-ga1_lrg.jpg] Functions of the PE-PPE family. A diagrammatic representation of the functions elicited by the proline-glutamic acid (PE)-proline-proline-glutamic acid (PPE) family proteins. Initially, the PE-PPE family due to its polymorphic and repetitive nature was considered a source of genetic and antigenic variation in Mycobacterium tuberculosis (M. tuberculosis) (Cole et al., 1998). However, PE-PPE proteins have since been assigned a wide range of diverse roles, which are outlined in the figure. The functions of the PE-PPE family are extensive, including modulating host immune responses, subverting host defence strategies, resisting diverse stresses of the host, and manipulating host cell fates, ultimately to ensure the survival of M. tuberculosis. The arrows indicate the PE-PPE-induced effects whereas the blunt-end arrows indicate the PE-PPE-inhibited effects. Chains of arrows and blunt-end arrows also highlight the functional pathways and consequential effects of PE-PPE-elicited functions. Abbreviations: cluster of differentiation (CD); major histocompatibility complex (MHC); interleukin (IL); interferon-gamma (IFN-ɣ); transforming growth factor-beta (TGF-β); tumour necrosis factor-alpha (TNF-α); sodium dodecyl-sulfate (SDS); polymorphic GC-rich (PE-PGRS); major polymorphic tandem repeat (MPTR).