RNF144A promotes antiviral responses by modulating STING ubiquitination

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Stimulator of interferon genes (STING) is critical for innate immune responses to cytosolic DNA and DNA viruses.
• The precise mechanisms regulating STING activation and downstream signaling remain an active area of research.

Purpose of the Study:

• To identify novel regulators of STING-mediated innate immunity.
• To elucidate the role of RING-finger protein (RNF) 144A in STING signaling and antiviral responses.

Main Methods:

• Co-immunoprecipitation assays to confirm protein interactions.
• Ubiquitination assays to identify ubiquitination sites and linkage types.
• Western blotting and reporter assays to assess STING translocation and downstream signaling.
• Cellular and animal models to evaluate RNF144A's role in antiviral immunity.

Main Results:

• RNF144A directly interacts with STING and promotes its K6-linked ubiquitination at K236.
• RNF144A enhances STING translocation from the ER to the Golgi, boosting downstream signaling.
• STING K236R mutant shows reduced activity, highlighting the importance of this ubiquitination site.
• Overexpression of RNF144A enhances antiviral responses, while RNF144A deficiency impairs them.
• RNF144A specifically regulates DNA virus-triggered immunity, not RNA virus responses.

Conclusions:

• RNF144A is a novel positive regulator of DNA virus- and cytosolic DNA-triggered innate immune signaling.
• K6-linked ubiquitination of STING at K236 by RNF144A is essential for robust antiviral responses.
• RNF144A plays a protective role against DNA virus infections in vivo.