Many pathogens have evolved sophisticated strategies to evade autophagy, a crucial cellular defense mechanism that typically targets and degrades invading microorganisms. By subverting or inhibiting autophagy, these pathogens can create a more favorable environment for their replication and survival within the host. For instance, some bacteria secrete factors that block autophagosome formation, while others might escape from autophagosomes before degradation. These evasion tactics are critical for the pathogens' ability to establish and maintain infections. Understanding the mechanisms by which pathogens avoid autophagy is crucial for developing new therapeutic strategies, as enhancing autophagy could bolster the host's immune response and aid in the elimination of pathogenic bacteria. Francisella tularensis can manipulate host cell pathways to prevent its detection and destruction by autophagy, thereby enhancing its virulence. Given the potential for F. tularensis to be used as a bioterrorism agent due to its high infectivity and ability to cause severe disease, research into how this pathogen evades autophagy is of critical importance. By unraveling these mechanisms, new therapeutic approaches could be developed to enhance autophagic responses and strengthen host defense against this and other similarly evasive pathogens.

• Keywords
• Francisella, autophagy, bacterial pathogenesis, host-pathogen interaction, virulence,
• MeSH
• Autophagy * MeSH
• Virulence Factors metabolism   MeSH
• Francisella tularensis * pathogenicity   immunology   physiology   MeSH
• Immune Evasion * MeSH
• Host-Pathogen Interactions * MeSH
• Humans MeSH
• Tularemia microbiology   immunology   MeSH
• Virulence MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Virulence Factors MeSH

Francisella tularensis influences several host molecular/signaling pathways during infection. Ubiquitination and deubiquitination are among the most important regulatory mechanisms and respectively occur through attachment or removal of the ubiquitin molecule. The process is necessary not only to mark molecules for degradation, but also, for example, to the activation of signaling pathways leading to pro-inflammatory host response. Many intracellular pathogens, including Francisella tularensis, have evolved mechanisms of modifying such host immune responses to escape degradation. Here, we describe that F. tularensis interferes with the host's ubiquitination system. We show increased total activity of deubiquitinating enzymes (DUBs) in human macrophages after infection, while confirm reduced enzymatic activities of two specific DUBs (USP10 and UCH-L5), and demonstrate increased activity of USP25. We further reveal the enrichment of these three enzymes in exosomes derived from F. tularensis-infected cells. The obtained results show the regulatory effect on ubiquitination mechanism in macrophages during F. tularensis infection.

• Keywords
• DUBs, Francisella, UCH-L5, USP10, USP25, deubiquitination, exosomes, extracellular vesicles,
• MeSH
• Deubiquitinating Enzymes metabolism   MeSH
• Francisella tularensis * MeSH
• Gram-Negative Bacterial Infections * metabolism   MeSH
• Humans MeSH
• Macrophages MeSH
• Signal Transduction MeSH
• Ubiquitin Thiolesterase metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Deubiquitinating Enzymes MeSH
• Ubiquitin Thiolesterase MeSH
• USP10 protein, human MeSH Browser
• USP25 protein, human MeSH Browser