Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• Interferon-stimulated gene 15 (ISG15) is an ubiquitin-like protein involved in antiviral responses through ISGylation.
• The precise mechanisms of ISG15 action and its interacting partners remain largely unknown.
• Ring Finger Protein 213 (RNF213) is an interferon-induced protein linked to Moyamoya disease, but its cellular functions are poorly understood.

Purpose of the Study:

• To identify ISG15-binding proteins and elucidate the role of ISG15 in innate immunity.
• To characterize the function of Ring Finger Protein 213 (RNF213) in the context of ISGylation and antimicrobial defense.
• To investigate the molecular mechanisms by which RNF213 mediates antiviral activity.

Main Methods:

• Virus-like particle trapping technology was employed to identify ISG15 interactors.
• Co-localization studies were performed to assess the cellular localization of RNF213.
• In vitro and in vivo assays were utilized to evaluate the antimicrobial activity of RNF213 against various pathogens.

Main Results:

• Ring Finger Protein 213 (RNF213) was identified as an ISG15-binding protein and a sensor of ISGylated proteins.
• Interferon stimulation induces ISGylation and oligomerization of RNF213 on lipid droplets.
• RNF213 demonstrated broad-spectrum antimicrobial activity against bacteria and viruses, including Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus, and coxsackievirus B3.

Conclusions:

• RNF213 acts as a crucial antimicrobial effector by sensing ISGylated proteins.
• The findings provide new molecular insights into the ISGylation pathway and its role in combating microbial infections.
• RNF213 is implicated as a key player in the host defense against a range of pathogens.