Lysine methylation shields an intracellular pathogen from ubiquitylation and autophagy

Area of Science:

• Microbiology
• Cell Biology
• Immunology

Background:

• Intracellular pathogens often evade host immune responses.
• Ubiquitylation is a key step in initiating antimicrobial autophagy.
• The mechanisms by which pathogens avoid ubiquitylation are not fully understood.

Purpose of the Study:

• To investigate how Rickettsia parkeri avoids ubiquitylation and subsequent autophagic targeting.
• To identify bacterial factors involved in evading host immune detection.

Main Methods:

• Genetic manipulation of Rickettsia parkeri to create mutants deficient in protein-lysine methyltransferases (PKMTs).
• In vivo studies using mouse models to assess virulence.
• In vitro studies using macrophages to evaluate bacterial growth and survival.
• Proteomic analysis of the bacterial lysine-methylome.

Main Results:

• PKMT-deficient Rickettsia parkeri mutants were avirulent in mice and failed to proliferate in macrophages.
• These mutants exhibited increased ubiquitylation and were targeted for autophagic degradation.
• Lysine methylation by PKMTs protected the outer membrane protein OmpB from ubiquitylation and surface depletion.
• PKMTs were found to methylate specific sites on OMPs, including OmpB, which are also targeted by host ubiquitin.

Conclusions:

• Lysine methylation is crucial for Rickettsia parkeri pathogenesis.
• Bacterial lysine methylation acts as a mechanism to shield bacterial proteins from ubiquitylation.
• This evasion of ubiquitylation allows the pathogen to escape autophagic targeting and establish infection.