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

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 int...

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Autores principales: Strong, Emily J., Ng, Tony W., Porcelli, Steven A., Lee, Sunhee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386380/
https://www.ncbi.nlm.nih.gov/pubmed/34346699
http://dx.doi.org/10.1128/mSphere.00549-21
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author Strong, Emily J.
Ng, Tony W.
Porcelli, Steven A.
Lee, Sunhee
author_facet Strong, Emily J.
Ng, Tony W.
Porcelli, Steven A.
Lee, Sunhee
author_sort Strong, Emily J.
collection PubMed
description 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 mycobacterial effectors that directly interact with host proteins responsible for autophagy initiation. IMPORTANCE Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which then resides and replicates mainly within host phagocytic cells. Autophagy is a complex host cellular process that helps control intracellular infections and enhance innate and adaptive immune responses. During coevolution with humans, M. tuberculosis has acquired various mechanisms to inhibit host cellular processes, including autophagy. We identified two related M. tuberculosis proteins, PE_PGRS20 and PE_PGRS47, as the first reported examples of specific mycobacterial effectors interfering with the initiation stage of autophagy. Autophagy regulation by these PE_PGRS proteins leads to increased bacterial survival in phagocytic cells and increased autophagic degradation of mycobacterial antigens to stimulate adaptive immune responses. A better understanding of how M. tuberculosis regulates autophagy in host cells could facilitate the design of new and more effective therapeutics or vaccines against tuberculosis.
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spelling pubmed-83863802021-09-09 Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A Strong, Emily J. Ng, Tony W. Porcelli, Steven A. Lee, Sunhee mSphere Research Article 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 mycobacterial effectors that directly interact with host proteins responsible for autophagy initiation. IMPORTANCE Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which then resides and replicates mainly within host phagocytic cells. Autophagy is a complex host cellular process that helps control intracellular infections and enhance innate and adaptive immune responses. During coevolution with humans, M. tuberculosis has acquired various mechanisms to inhibit host cellular processes, including autophagy. We identified two related M. tuberculosis proteins, PE_PGRS20 and PE_PGRS47, as the first reported examples of specific mycobacterial effectors interfering with the initiation stage of autophagy. Autophagy regulation by these PE_PGRS proteins leads to increased bacterial survival in phagocytic cells and increased autophagic degradation of mycobacterial antigens to stimulate adaptive immune responses. A better understanding of how M. tuberculosis regulates autophagy in host cells could facilitate the design of new and more effective therapeutics or vaccines against tuberculosis. American Society for Microbiology 2021-08-04 /pmc/articles/PMC8386380/ /pubmed/34346699 http://dx.doi.org/10.1128/mSphere.00549-21 Text en Copyright © 2021 Strong et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Strong, Emily J.
Ng, Tony W.
Porcelli, Steven A.
Lee, Sunhee
Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title_full Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title_fullStr Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title_full_unstemmed Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title_short Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A
title_sort mycobacterium tuberculosis pe_pgrs20 and pe_pgrs47 proteins inhibit autophagy by interaction with rab1a
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386380/
https://www.ncbi.nlm.nih.gov/pubmed/34346699
http://dx.doi.org/10.1128/mSphere.00549-21
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