Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Chikungunya virus (CHIKV) causes debilitating arthritis and arthralgia.
• Host RNA sensing pathways are understood, but cytosolic DNA sensing antagonism by CHIKV is less clear.
• The cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway detects cytosolic DNA.

Purpose of the Study:

• To investigate the role of the cGAS-STING pathway in restricting CHIKV replication.
• To elucidate the mechanisms by which CHIKV antagonizes this DNA sensing pathway.

Main Methods:

• Utilized cGAS or STING null cells to assess CHIKV replication.
• Detected cytoplasmic DNA accumulation and inhibited DNA-dependent IFN-β transcription.
• Investigated CHIKV capsid protein and nsP1 interactions with cGAS and STING, respectively.

Main Results:

• The cGAS-STING pathway restricts CHIKV replication in fibroblasts and immune cells.
• CHIKV induces autophagy-mediated degradation of cGAS, with the capsid protein sufficient for this effect.
• CHIKV nsP1 interacts with STING, stabilizing nsP1 and increasing its palmitoylation.

Conclusions:

• CHIKV actively antagonizes the cGAS-STING DNA sensing pathway.
• Autophagy-mediated degradation of cGAS and nsP1 interaction with STING are key viral antagonism mechanisms.
• This work highlights the cGAS-STING pathway's role in detecting (+)ssRNA viruses and CHIKV's evasion strategies.