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Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum-infected macrophages

Nobs, Esther LU ; Laschanzky, Katie LU orcid ; Munke, Kristina LU ; Movert, Elin LU ; Valfridsson, Christine LU and Carlsson, Fredric LU orcid (2024) In mBio 15(9).
Abstract

UNLABELLED: Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo. Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g, two cytosolic serpins of the clade A3. The... (More)

UNLABELLED: Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo. Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g, two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture.

IMPORTANCE: The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates serpina3f and serpina3g and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth in vivo. The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.

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organization
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publication status
published
subject
keywords
Animals, Female, Mice, Bacterial Proteins/metabolism, Cell Death, Cytosol/microbiology, Feedback, Physiological, Host-Pathogen Interactions, Interferon Type I/metabolism, Macrophages/microbiology, Mice, Inbred C57BL, Mycobacterium Infections, Nontuberculous/microbiology, Mycobacterium marinum/pathogenicity, Serpins/metabolism, Signal Transduction, Type VII Secretion Systems/metabolism
in
mBio
volume
15
issue
9
article number
e0038424
publisher
American Society for Microbiology
external identifiers
  • pmid:39087767
  • scopus:85203872794
ISSN
2161-2129
DOI
10.1128/mbio.00384-24
language
English
LU publication?
yes
id
60d7913b-f9db-477b-bb83-a3796a23058b
date added to LUP
2024-10-10 15:52:54
date last changed
2025-07-05 03:35:10
@article{60d7913b-f9db-477b-bb83-a3796a23058b,
  abstract     = {{<p>UNLABELLED: Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo. Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g, two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture.</p><p>IMPORTANCE: The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates serpina3f and serpina3g and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth in vivo. The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.</p>}},
  author       = {{Nobs, Esther and Laschanzky, Katie and Munke, Kristina and Movert, Elin and Valfridsson, Christine and Carlsson, Fredric}},
  issn         = {{2161-2129}},
  keywords     = {{Animals; Female; Mice; Bacterial Proteins/metabolism; Cell Death; Cytosol/microbiology; Feedback, Physiological; Host-Pathogen Interactions; Interferon Type I/metabolism; Macrophages/microbiology; Mice, Inbred C57BL; Mycobacterium Infections, Nontuberculous/microbiology; Mycobacterium marinum/pathogenicity; Serpins/metabolism; Signal Transduction; Type VII Secretion Systems/metabolism}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{9}},
  publisher    = {{American Society for Microbiology}},
  series       = {{mBio}},
  title        = {{Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum-infected macrophages}},
  url          = {{http://dx.doi.org/10.1128/mbio.00384-24}},
  doi          = {{10.1128/mbio.00384-24}},
  volume       = {{15}},
  year         = {{2024}},
}