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

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

doi:10.1128/msphere.00549-21

Cited by 35 publications

(24 citation statements)

References 63 publications

(109 reference statements)

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“… 2016 ; Strong et al . 2021 ). Under basal autophagy conditions, PE_PGRS47-deficient H37Rv was susceptible to autophagy-mediated elimination, resulting in enhanced autophagy-mediated MHC-II antigen presentation (Saini et al .…”

Section: Discussionmentioning

confidence: 99%

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The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction

Siregar

Prombutara

Kanjanasirirat

et al. 2022

Pathogens and Disease

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Mycobacterium tuberculosis utilizes several mechanisms to block phagosome-lysosome fusion to evade host cell restriction. However, induction of host cell autophagy by starvation was shown to overcome this block, resulting in enhanced lysosomal delivery to mycobacterial phagosomes and the killing of the M. tuberculosis reference strain H37Rv. Nevertheless, our previous studies found that strains belonging to the M. tuberculosis Beijing genotype can resist starvation-induced autophagic elimination, though the mycobacterial factors involved remain unclear. In this study, we showed that KatG expression is upregulated in the autophagy-resistant M. tuberculosis Beijing strain (BJN) during autophagy induction by the starvation of host macrophages, while such increase was not observed in the H37Rv. KatG depletion using the CRISPR-dCas9 interference system in the BJN resulted in increased lysosomal delivery to its phagosome and decreased its survival upon autophagy induction by starvation. As KatG functions by catabolizing ROS, we determined the source of ROS contributing to the starvation-induced autophagic elimination of mycobacteria. Using siRNA-mediated knockdown, we found that Superoxide dismutase 2, which generates mitochondrial ROS but not NADPH oxidase 2, is important for the starvation-induced lysosomal delivery to mycobacterial phagosomes. Taken together, these findings showed that KatG is vital for the BJN to evade starvation-induced autophagic restriction.

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Section: Discussionmentioning

confidence: 99%

“… 2016 ; Strong et al . 2021 ). However, the dampening effect of PE_PGRS47 on the autophagy-mediated MHC-II antigen presentation mentioned above was eliminated when autophagy was induced by rapamycin treatment of host cells (Saini et al .…”

Section: Discussionmentioning

confidence: 99%

The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction

Siregar

Prombutara

Kanjanasirirat

et al. 2022

Pathogens and Disease

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“…To confirm our previous findings using a transposon mutant with a mutation in the ppe51 gene ( 30 ), we used Δ 51 to assay autophagy and bacterial survival in macrophages. Autophagy was increased in the RAW 264.7 macrophage cell line infected with Δ 51 compared to WT or Δ 51 C infection ( Fig.…”

Section: Resultsmentioning

confidence: 81%

“…Alternatively to canonical autophagy inhibition, PknG induces canonical autophagy but inhibits autophagy flux by targeting Rab14 ( 29 ). Our recent studies also demonstrated that PE_PGRS20 and PE_PGRS47 inhibit autophagy in macrophages via association with Rab1A ( 30 ).…”

Section: Introductionmentioning

confidence: 82%

“…Middlebrook 7H10 agar medium was supplemented with 10% OADC and 0.5% glycerol with or without antibiotics as per requirements (hygromycin, 50 μg/mL, and kanamycin, 25 μg/mL). Recombinant M. smegmatis strains expressing PPE51 (Msm::51) and the Mtb ppe51 genetic deletion (Δ 51 ) were described previously ( 12 , 30 ). Briefly, recombinant strains were generated by amplifying full-length ppe51 from Mtb genomic DNA and cloned in frame into pMV261 ( 67 ), an episomal mycobacterial vector with a 3′ His6-HA tag and an hsp60 promoter.…”

Section: Methodsmentioning

confidence: 99%

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Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling

Strong

Wang

et al. 2022

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The C‐terminal extension of VgrG4 from Klebsiella pneumoniae remodels host cell microfilaments

et al. 2022

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Klebsiella pneumoniae is an opportunistic pathogen, which concerns public health systems worldwide, as multiple antibiotic-resistant strains are frequent. One of its pathogenicity factors is the Type VI Secretion System (T6SS), a macromolecular complex assembled through the bacterial membranes. T6SS injects effector proteins inside target cells. Such effectors confer competitive advantages or modulate the target cell signaling and metabolism to favor bacterial infection. The VgrG protein is a T6SS core component. It may present a variable C-terminal domain carrying an additional effector function. Kp52.145 genome encodes three VgrG proteins, one of them with a C-terminal extension (VgrG4-CTD). VgrG4-CTD is 138 amino acids long, does not contain domains of known function, but is conserved in some Klebsiella, and non-Klebsiella species. To get insights into its function, recombinant VgrG4-CTD was used in pulldown experiments to capture ligands from macrophages and lung epithelial cells. A total of 254 proteins were identified: most of them are ribosomal proteins.Cytoskeleton-associated and proteins involved in the phagosome maturation pathway were also identified. We further showed that VgrG4-CTD binds actin and induces actin remodeling in macrophages. This study presents novel clues on the role of K. pneumoniae T6SS in pathogenesis.bacterium-host interactions, cytoskeleton, protein-protein interactions, proteomics, T6SS | INTRODUCTIONKlebsiella pneumoniae is a gram-negative encapsulated member of the Enterobacteriaceae family. This species is ubiquitous in nature, and frequently associated with animals and humans. 1 On one hand, there are the classical pathogenic strains mainly affecting immune-compromised or hospitalized individuals, causing infections in the urinary and respiratory tracts, as well as bacteremia. Frequently, those strains are multiple antibiotic-resistant. 2 In another hand, there are hypervirulent strains that may cause acute community-acquired infections.

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

Cited by 35 publications

References 63 publications

The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction

The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction

Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling

The C‐terminal extension of VgrG4 from Klebsiella pneumoniae remodels host cell microfilaments

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