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TitleNucleic-acid-induced ZCCHC3 condensation promotes broad innate immune responses.
Journal, issue, pagesMol Cell, Vol. 85, Issue 5, Page 962-975.e7, Year 2025
Publish dateMar 6, 2025
AuthorsMiao Shi / Tao Jiang / Mengfan Zhang / Quanjin Li / Kexin Liu / Ni Lin / Xinlu Wang / Amin Jiang / Yina Gao / Yong Wang / Songqing Liu / Liguo Zhang / Dong Li / Pu Gao /
PubMed AbstractRetinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and cyclic GMP-AMP synthase (cGAS) recognize aberrant nucleic acids and initiate antiviral responses. Host factor zinc finger CCHC domain- ...Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and cyclic GMP-AMP synthase (cGAS) recognize aberrant nucleic acids and initiate antiviral responses. Host factor zinc finger CCHC domain-containing protein 3 (ZCCHC3) positively regulates both RLRs- and cGAS-mediated signaling through unknown mechanisms. Here, we show that ZCCHC3 employs a broad and unified strategy to promote these pathways in human cell lines. Rather than developing strong protein-protein interactions, ZCCHC3 harbors multiple nucleic-acid-binding modules and undergoes robust liquid phase condensation with nucleic acids. RNA-induced ZCCHC3 condensates enrich and activate RLRs, which then facilitate the interaction of RLRs with the downstream adaptor mitochondrial antiviral-signaling (MAVS). Direct and high-resolution structure determination of liquid condensates confirms the assembly of active-form MAVS filaments. Furthermore, ZCCHC3 efficiently promotes the condensation and enrichment of DNA, cGAS, ATP, and GTP, thereby enhancing cGAS signaling. ZCCHC3 mutants defective in RNA/DNA-induced condensation lost their regulatory efficiency in both pathways. These results highlight unexpectedly broad connections between biomolecular condensation and innate immunity.
External linksMol Cell / PubMed:39983719
MethodsEM (single particle)
Resolution3.21 Å
Structure data

37609

8wkw

EMDB-37609, PDB-8wkw:
Structure of MAVS-CARD Filament
Method: EM (single particle) / Resolution: 3.21 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / Filament

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