ISG15 is counteracted by vaccinia virus E3 protein and controls the proinflammatory response against viral infection

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Interferon-stimulated gene 15 (ISG15) conjugation, known as ISGylation, is a post-translational modification that plays a critical role in antiviral defense.
• Several viruses are known to be inhibited by ISG15 conjugation.
• The vaccinia virus E3 protein is a known virulence factor that can interfere with host antiviral mechanisms.

Purpose of the Study:

• To investigate the interaction between vaccinia virus E3 protein and the ISGylation machinery.
• To determine the role of ISGylation in poxvirus infection using a mouse model.
• To elucidate the specific functions of conjugated and unconjugated ISG15 in the context of vaccinia virus infection.

Main Methods:

• Utilized an expression system to assay human and mouse ISG15 conjugations (ISGylations).
• Demonstrated binding and antagonism of ISG15 modification by vaccinia virus E3 protein.
• Employed a mouse model expressing deconjugating proteases to study ISGylation's importance in poxvirus infection.

Main Results:

• Vaccinia virus E3 protein was shown to bind and antagonize both human and mouse ISG15 modification.
• ISGylation was found to restrict the in vitro replication of the vaccinia virus VVΔE3L mutant.
• Unconjugated ISG15 was identified as crucial for counteracting the inflammatory response following VVΔE3L infection.

Conclusions:

• The vaccinia virus E3 protein directly interferes with the host antiviral ISGylation pathway.
• ISGylation is an important antiviral mechanism against vaccinia virus, particularly for restricting viral replication.
• Both conjugated and unconjugated forms of ISG15 have distinct roles in antiviral immunity, with unconjugated ISG15 being critical for immune regulation during infection.