A Phospho-SIM in the Antiviral Protein PML is Required for Its Recruitment to HSV-1 Genomes

Area of Science:

• Virology
• Cellular Biology
• Immunology

Background:

• Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen.
• Cells possess intrinsic and innate defenses against viral replication, including the promyelocytic leukemia (PML) protein.
• PML protein, a component of nuclear domain 10 (ND10), plays a role in antiviral responses, but the impact of its phosphorylation on HSV-1 defense is unclear.

Purpose of the Study:

• To investigate the role of phosphorylation in regulating the antiviral activity of PML protein against HSV-1.
• To identify specific phosphorylation sites on PML isoform I (PML-I) that affect its antiviral function.

Main Methods:

• Phosphorylation sites on PML were mapped.
• Mutations were introduced at known and identified phosphorylation sites on PML-I.
• The effects of these mutations on PML-I's antiviral activities and interactions were assessed.

Main Results:

• Phosphorylation at most sites on PML-I is not essential for ND10 formation or colocalization with HSV-1 ICP0.
• Inhibiting phosphorylation at sites near the SUMO-interaction motif (SIM) of PML-I significantly impairs its response to HSV-1 infection.
• PML-I's ability to antagonize HSV-1 replication is modulated by specific phosphorylation events.

Conclusions:

• PML phosphorylation plays a regulatory role in the cellular antiviral response against HSV-1.
• Specific phosphorylation sites, particularly those near the SIM, are critical for PML's antiviral efficacy.
• Understanding PML phosphorylation offers insights into host-pathogen interactions and potential therapeutic targets.