Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease

ABSTRACT Tuberculosis, one of the world’s most severe infectious diseases, is caused by Mycobacterium tuberculosis. A major weapon of this pathogen is a unique cell wall that protects the pathogen from eradication by the immune system. Mycobacteria have specialized secretion systems, e.g., type VII...

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Autores principales:	Maroeska J. Burggraaf, Alexander Speer, Aniek S. Meijers, Roy Ummels, Astrid M. van der Sar, Konstantin V. Korotkov, Wilbert Bitter, Coenraad Kuijl
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	aspartic protease Mycobacterium PE proteins PE_PGRS type VII secretion Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/471da19eeb16404ebd6a78080b66c8b0
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spelling	oai:doaj.org-article:471da19eeb16404ebd6a78080b66c8b02021-11-15T15:59:42ZType VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease10.1128/mBio.01951-192150-7511https://doaj.org/article/471da19eeb16404ebd6a78080b66c8b02019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01951-19https://doaj.org/toc/2150-7511ABSTRACT Tuberculosis, one of the world’s most severe infectious diseases, is caused by Mycobacterium tuberculosis. A major weapon of this pathogen is a unique cell wall that protects the pathogen from eradication by the immune system. Mycobacteria have specialized secretion systems, e.g., type VII secretion or ESX systems, to transport substrates across this cell wall. The largest group of proteins that are secreted by these ESX systems are the PE proteins. Previously, it was shown that the N-terminal PE domain of about 100 amino acids is required for secretion. Here, we describe the identification of an aspartic protease, designated PecA, that removes (part of) this PE domain at the cell surface. Nearly all of the observed PE_PGRS proteins are processed by PecA. Interestingly, the protease itself is also a secreted PE protein and subject to self-cleavage. Furthermore, a defect in surface processing has no effect on the activity of the PE lipase protein LipY but does seem to affect the functioning of other virulence factors, as a pecA mutant strain of Mycobacterium marinum shows moderate attenuation in zebrafish larvae. In conclusion, our results reveal the presence of a functional aspartic acid protease in M. marinum that cleaves LipY, itself as well as other members of the PE_PGRS family. Finally, mutants lacking PecA show growth attenuation in vivo, suggesting that PecA plays a role during infection. IMPORTANCE Aspartic proteases are common in eukaryotes and retroviruses but are relatively rare among bacteria (N. D. Rawlings and A. Bateman, BMC Genomics 10:437, 2009, https://doi.org/10.1186/1471-2164-10-437). In contrast to eukaryotic aspartic proteases, bacterial aspartic proteases are generally located in the cytoplasm. We have identified a surface-associated mycobacterial aspartic protease, PecA, which cleaves itself and many other type VII secretion substrates of the PE_PGRS family. PecA is present in most pathogenic mycobacterial species, including M. tuberculosis. In addition, pathogenicity of M. marinum is reduced in the ΔpecA mutant, indicating that PecA contributes to virulence.Maroeska J. BurggraafAlexander SpeerAniek S. MeijersRoy UmmelsAstrid M. van der SarKonstantin V. KorotkovWilbert BitterCoenraad KuijlAmerican Society for Microbiologyarticleaspartic proteaseMycobacteriumPE proteinsPE_PGRStype VII secretionMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	aspartic protease Mycobacterium PE proteins PE_PGRS type VII secretion Microbiology QR1-502
spellingShingle	aspartic protease Mycobacterium PE proteins PE_PGRS type VII secretion Microbiology QR1-502 Maroeska J. Burggraaf Alexander Speer Aniek S. Meijers Roy Ummels Astrid M. van der Sar Konstantin V. Korotkov Wilbert Bitter Coenraad Kuijl Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
description	ABSTRACT Tuberculosis, one of the world’s most severe infectious diseases, is caused by Mycobacterium tuberculosis. A major weapon of this pathogen is a unique cell wall that protects the pathogen from eradication by the immune system. Mycobacteria have specialized secretion systems, e.g., type VII secretion or ESX systems, to transport substrates across this cell wall. The largest group of proteins that are secreted by these ESX systems are the PE proteins. Previously, it was shown that the N-terminal PE domain of about 100 amino acids is required for secretion. Here, we describe the identification of an aspartic protease, designated PecA, that removes (part of) this PE domain at the cell surface. Nearly all of the observed PE_PGRS proteins are processed by PecA. Interestingly, the protease itself is also a secreted PE protein and subject to self-cleavage. Furthermore, a defect in surface processing has no effect on the activity of the PE lipase protein LipY but does seem to affect the functioning of other virulence factors, as a pecA mutant strain of Mycobacterium marinum shows moderate attenuation in zebrafish larvae. In conclusion, our results reveal the presence of a functional aspartic acid protease in M. marinum that cleaves LipY, itself as well as other members of the PE_PGRS family. Finally, mutants lacking PecA show growth attenuation in vivo, suggesting that PecA plays a role during infection. IMPORTANCE Aspartic proteases are common in eukaryotes and retroviruses but are relatively rare among bacteria (N. D. Rawlings and A. Bateman, BMC Genomics 10:437, 2009, https://doi.org/10.1186/1471-2164-10-437). In contrast to eukaryotic aspartic proteases, bacterial aspartic proteases are generally located in the cytoplasm. We have identified a surface-associated mycobacterial aspartic protease, PecA, which cleaves itself and many other type VII secretion substrates of the PE_PGRS family. PecA is present in most pathogenic mycobacterial species, including M. tuberculosis. In addition, pathogenicity of M. marinum is reduced in the ΔpecA mutant, indicating that PecA contributes to virulence.
format	article
author	Maroeska J. Burggraaf Alexander Speer Aniek S. Meijers Roy Ummels Astrid M. van der Sar Konstantin V. Korotkov Wilbert Bitter Coenraad Kuijl
author_facet	Maroeska J. Burggraaf Alexander Speer Aniek S. Meijers Roy Ummels Astrid M. van der Sar Konstantin V. Korotkov Wilbert Bitter Coenraad Kuijl
author_sort	Maroeska J. Burggraaf
title	Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
title_short	Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
title_full	Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
title_fullStr	Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
title_full_unstemmed	Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease
title_sort	type vii secretion substrates of pathogenic mycobacteria are processed by a surface protease
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/471da19eeb16404ebd6a78080b66c8b0
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Type VII Secretion Substrates of Pathogenic Mycobacteria Are Processed by a Surface Protease

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