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Mycoplasma glycine cleavage system key subunit GcvH is an apoptosis inhibitor targeting host endoplasmic reticulum
Qiao Pan1, Yujuan Zhang1, Tong Liu1
1State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
Abstract:
Mycoplasmas are minimal but notorious bacteria that infect humans and animals. These genome-reduced organisms have evolved strategies to overcome host apoptotic defense and establish persistent infection. Here, using Mycoplasma bovis as a model, we demonstrate that mycoplasma glycine cleavage system (GCS) H protein (GcvH) targets the endoplasmic reticulum (ER) to hijack host apoptosis facilitating bacterial infection. Mechanically, GcvH interacts with the ER-resident kinase Brsk2 and stabilizes it by blocking its autophagic degradation. Brsk2 subsequently disturbs unfolded protein response (UPR) signaling, thereby inhibiting the key apoptotic molecule CHOP expression and ER-mediated intrinsic apoptotic pathway. CHOP mediates a cross-talk between ER- and mitochondria-mediated intrinsic apoptosis. The GcvH N-terminal amino acid 31-35 region is necessary for GcvH interaction with Brsk2, as well as for GcvH to exert anti-apoptotic and potentially pro-infective functions. Notably, targeting Brsk2 to dampen apoptosis may be a conserved strategy for GCS-containing mycoplasmas. Our study reveals a novel role for the conserved metabolic route protein GcvH in Mycoplasma species. It also sheds light on how genome-reduced bacteria exploit a limited number of genomic proteins to resist host cell apoptosis thereby facilitating pathogenesis.
Insights
Mycoplasma bovis GcvH protein targets the endoplasmic reticulum to inhibit host cell apoptosis, aiding bacterial infection. This mechanism involves stabilizing Brsk2 kinase, disrupting unfolded protein response, and preventing cell death.
Area of Science:
- Microbiology
- Cell Biology
- Bacterial Pathogenesis
Background:
- Mycoplasmas are minimal, genome-reduced bacteria known for causing persistent infections in humans and animals.
- These pathogens possess strategies to evade host apoptotic defenses, crucial for establishing infection.
Purpose of the Study:
- To investigate the mechanism by which Mycoplasma bovis evades host apoptosis.
- To identify specific bacterial proteins involved in manipulating host cell death pathways.
Main Methods:
- Utilized Mycoplasma bovis as a model organism.
- Investigated the interaction of mycoplasma glycine cleavage system H protein (GcvH) with host endoplasmic reticulum (ER) proteins.
- Analyzed the role of Brsk2 kinase and unfolded protein response (UPR) signaling in apoptosis modulation.
- Identified the specific region of GcvH responsible for its anti-apoptotic function.
Main Results:
- Mycoplasma bovis GcvH protein targets the ER and interacts with the ER-resident kinase Brsk2.
- GcvH stabilizes Brsk2 by inhibiting its degradation, leading to disturbed UPR signaling.
- This interaction suppresses CHOP expression and the ER-mediated intrinsic apoptotic pathway.
- The N-terminal region (amino acids 31-35) of GcvH is essential for Brsk2 interaction and anti-apoptotic activity.
Conclusions:
- Mycoplasma GcvH protein is a novel virulence factor that hijacks host ER apoptosis for bacterial pathogenesis.
- Targeting Brsk2 to dampen apoptosis is a potentially conserved strategy among GCS-containing mycoplasmas.
- Genome-reduced bacteria like mycoplasmas exploit limited proteins to resist host cell apoptosis and facilitate infection.
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