Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A

Emily J. Strong, Tony W. Ng, Steven A. Porcelli, Sunhee Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Autophagy is a fundamental cellular process that has important roles in innate and adaptive immunity against a broad range of microbes. Many pathogenic microbes have evolved mechanisms to evade or exploit autophagy. It has been previously demonstrated that induction of autophagy can suppress the intracellular survival of mycobacteria, and several PE_PGRS family proteins of Mycobacterium tuberculosis have been proposed to act as inhibitors of autophagy to promote mycobacterial survival. However, the mechanisms by which these effectors inhibit autophagy have not been defined. Here, we report detailed studies of M. tuberculosis deletion mutants of two genes, pe_pgrs20 and pe_pgrs47, that we previously reported as having a role in preventing autophagy of infected host cells. These mutants resulted in increased autophagy and reduced intracellular survival of M. tuberculosis in macrophages. This phenotype was accompanied by increased cytokine production and antigen presentation by infected cells. We further demonstrated that autophagy inhibition by PE_PGRS20 and PE_PGRS47 resulted from canonical autophagy rather than autophagy flux inhibition. Using macrophages transfected to express PE_PGRS20 or PE_PGRS47, we showed that these proteins inhibited autophagy initiation directly by interacting with Ras-related protein Rab1A. Silencing of Rab1A in mammalian cells rescued the survival defects of the pe_pgrs20 and pe_pgrs47 deletion mutant strains and reduced cytokine secretion. To our knowledge, this is the first study to identify mycobacterialeffectors that directly interact with host proteins responsible for autophagy initiation.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalmSphere
Volume6
Issue number4
DOIs
StatePublished - Aug 2021

Keywords

  • autophagy
  • host-pathogen interactions
  • innate immunity
  • Mycobacterium tuberculosis
  • PE_PGRS proteins

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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