VZV IE4 downregulates cellular surface MHC-I via sequestering it to the Golgi complex

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Varicella-zoster virus (VZV) infection reduces surface major histocompatibility complex class I (MHC-I) expression.
• The precise mechanism by which VZV achieves this downregulation and Golgi retention of MHC-I remains unclear.
• The VZV IE4 protein is critical for VZV pathogenesis.

Purpose of the Study:

• To elucidate the mechanism of VZV-mediated MHC-I downregulation.
• To identify cellular factors interacting with VZV IE4.
• To investigate the role of IE4 in sequestering MHC-I and evading host immunity.

Main Methods:

• Co-immunoprecipitation and co-localization assays to identify and study IE4-HLA-C interaction.
• Generation of a VZV mutant (mIE4 VZV) with a disrupted Golgi localization signal in IE4.
• Analysis of surface MHC-I expression and HLA-C localization in infected cells.

Main Results:

• Human leucocyte antigen C (HLA-C) was identified as a novel cellular binding partner of VZV IE4.
• Ectopic IE4 expression led to co-localization with HLA-C and its retention in the Golgi complex, reducing surface MHC-I.
• Infection with mIE4 VZV restored surface MHC-I expression, as HLA-C was not retained in the Golgi.

Conclusions:

• VZV IE4 directly interferes with the MHC-I presentation pathway by sequestering HLA-C in the Golgi.
• This interaction is crucial for VZV-induced downregulation of surface MHC-I.
• The findings reveal a novel VZV immune evasion strategy targeting host antiviral adaptive immunity.