Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS.

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• The cGAS-cGAMP-STING pathway is vital for detecting cytosolic DNA and initiating antiviral responses.
• DNA viruses often evade cytosolic DNA sensors by entering the nucleus, where chromatin can limit cGAS activation.
• Mechanisms by which viruses activate nuclear cGAS are not fully understood.

Purpose of the Study:

• To investigate how herpesviruses activate the cGAS-cGAMP-STING pathway within the cell nucleus.
• To elucidate the role of centromeres in nuclear cGAS activation during viral infections.

Main Methods:

• Utilized cell-based assays to study herpesvirus protein interactions with centromeres.
• Investigated the impact of viral proteins, such as HSV-1 ICP0 and CMV IE1, on centromeric DNA and cGAS activation.
• Employed techniques to analyze DNA synthesis pathways, including translesion DNA synthesis (TLS).

Main Results:

• Several herpesvirus proteins were found to trigger nuclear cGAS activation by disrupting centromeres.
• Herpes simplex virus type 1 (HSV-1) ICP0 promotes centromeric DNA amplification via TLS, activating nuclear cGAS in quiescent cells.
• HSV-1 UL36USP suppresses TLS to evade this immune detection, while CMV IE1 also induces centromeric DNA amplification and cGAS activation.

Conclusions:

• Defined a novel mechanism termed viral-induced centromeric DNA amplification and recognition (VICAR).
• Demonstrated that centromeres play a non-mitotic, immune-activating role by serving as platforms for viral-induced DNA amplification and cGAS activation.
• Uncovered a new strategy employed by herpesviruses to manipulate host cell pathways for immune evasion.