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RNF39 facilitates antiviral immune responses by promoting K63-linked ubiquitination of STING

Wenwen Wang1, Qi Li2, Mutian Jia3

  • 1Department of Pathogenic Biology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Department of Clinical Laboratory, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.

International Immunopharmacology
|September 10, 2024
PubMed

Insights

RING finger protein 39 (RNF39) activates the STING protein, enhancing DNA sensing and antiviral immunity. RNF39 deficiency impairs immune responses to viral DNA infections, highlighting its therapeutic potential.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • The cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-STING pathway is crucial for detecting cytosolic DNA and initiating innate immune responses.
  • While STING is central to this pathway, the precise mechanisms regulating its activation remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the E3 ubiquitin ligase RING finger protein 39 (RNF39) in regulating the cGAS-STING pathway.
  • To elucidate the molecular mechanism by which RNF39 controls STING activation and innate immune responses.

Main Methods:

  • Co-immunoprecipitation assays to assess RNF39-STING interaction in macrophages and HERK293T cells.
  • Analysis of STING ubiquitination and STING-TBK1 complex formation.
  • Assessment of innate immune responses and viral replication in Rnf39-deficient cells and during herpes simplex virus-1 (HSV-1) infection.

Main Results:

  • RNF39 was found to interact with STING.
  • RNF39 promotes K63-linked ubiquitination of STING, facilitating STING-TBK1 complex formation and accelerating DNA-sensing pathways.
  • Rnf39 deficiency led to impaired innate immune responses against DNA viral infection and increased viral replication.
  • HSV-1 infection induced RNF39 expression in an IFN-I-dependent manner.

Conclusions:

  • RNF39 acts as a positive regulator of STING activation, enhancing DNA-sensing innate immune responses.
  • RNF39 plays a critical role in antiviral immunity, particularly against DNA viruses.
  • RNF39 represents a potential therapeutic target for viral diseases, especially those caused by DNA viruses.
Keywords:
Antiviral immunityInnate immunityRNF39STINGUbiquitination

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