FEZ1 phosphorylation regulates HSPA8 localization and interferon-stimulated gene expression

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Fasciculation and elongation protein zeta-1 (FEZ1) is a kinesin adaptor with diverse cellular roles.
• FEZ1 is implicated in neurodegeneration and viral infections.

Purpose of the Study:

• To investigate the role of FEZ1 in antiviral responses against large DNA viruses.
• To elucidate the molecular mechanisms underlying FEZ1's broad antiviral phenotype.

Main Methods:

• Modulation of FEZ1 expression in human cell lines (microglia, macrophages, fibroblasts).
• Analysis of interferon-stimulated genes (ISGs) and STING-independent pathways.
• Investigation of FEZ1 phosphorylation at S58 and its interaction with heat shock protein 8 (HSPA8) and DNA-dependent protein kinase (DNA-PK).

Main Results:

• FEZ1 modulates infection by large DNA viruses through pre-induction of ISGs, independent of STING.
• Phosphorylation at FEZ1 S58 regulates HSPA8 binding, localization, and ISG expression.
• FEZ1 and HSPA8 influence ISG expression via changes in nuclear DNA-PK accumulation.
• DNA stimulation reduces FEZ1 S58 phosphorylation and promotes nuclear translocation of HSPA8 and DNA-PK.

Conclusions:

• FEZ1 acts as a regulatory component in the HSPA8/DNA-PK innate immune pathway.
• FEZ1's phosphorylation status is critical for its function in antiviral immunity.
• The HSPA8/DNA-PK pathway represents a novel innate immune mechanism modulated by FEZ1.