Researchers Discover a Novel Molecular Mechanism that Regulates Endogenous dsRNA Homeostasis

Double-stranded RNAs (dsRNAs) adopt an A-form duplex structure, characterized by narrow major grooves and wide minor grooves. These molecules are often generated during virus infections and activate innate immune response in host cells. Under specific pathological conditions, cells may overproduce endogenous dsRNA, triggering cellular stress responses. The recognition and response to dsRNA play pivotal roles in processes such as viral infections, autoimmune diseases, and malignant tumors; however, the underlying molecular mechanisms remain largely unclear.

Recently, the research group led by Dr. Ruibing Chen and Dr. Xin Mu from the School of Pharmaceutical Science and Technology (SPST), Faculty of Medicine, Tianjin University published a research article in Nature Communicationstitled as "Characterization of dsRNA Binding Proteins through Solubility Analysis Identifies ZNF385A as a dsRNA Homeostasis Regulator". This study established a novel method for identifying dsRNA binding proteins (dsRBPs) through proteome integral solubility alteration analysis. Based on this approach, the team discovered a zinc finger protein ZNF385A as a novel dsRBP that plays a critical role in maintaining endogenous dsRNA homeostasis.

The Chen group has been devoted to the development of mass spectrometry-based analytical methods for characterizing RNA-binding proteins and to understand the molecular mechanisms (Nat Commun 2020, Mol Cell Proteomics 2021, Anal Chim Acta 2021, Nucleic Acids Res 2017), providing new insights into the biological significance of the interactions between RNAs and proteins. In this study, the team observed that dsRNA induced solubility changes of the proteins they bound with once heated at different temperatures. Leveraging this principle, they developed a new strategy for large-scale dsRBP characterization, expanding the known repertoire of dsRBPs.

Subsequently, the team focused on the newly identified dsRBP, ZNF385A. They found that its knockout activated interferon signaling pathways in lung epithelial cell and multiple tumor cell lines. ZNF385A knockout led to intracellular dsRNA accumulation, and dsRNA immunoprecipitation sequencing (dsRIP-seq) revealed that these dsRNAs mainly originated from retroelements, such as short interspersed nuclear element. Furthermore, targeting ZNF385A could enhance the biological activity of DNA methyltransferase inhibitor 5-AZA-CdR and NK cell cytotoxicity, highlighting the potential value of targeting ZNF385A in cancer treatment.

By School of Pharmaceutical Science and Technology

Editor: Sun Xiaofang