C19ORF25

C19orf25 is a functionally uncharacterized gene implicated in restraining STING-dependent innate immune signaling through a role in Golgi-to-ER retrograde transport (PMID:39657680, PMID:38645119). In a genome-wide optical pooled CRISPR screen scoring subcellular STING localization, loss of C19orf25 enhanced STING signaling, and C19orf25 co-clustered phenotypically with USE1, a Golgi-to-ER retrograde transport factor, placing it in a transport pathway that normally limits STING activity (PMID:39657680, PMID:38645119). Beyond this genetic and phenotypic association (PMID:39657680, PMID:38645119), no direct molecular activity, binding partner, or biochemical mechanism for C19orf25 has been characterized in the available corpus.

1. 2024 Medium

   Whether C19orf25 has any defined cellular role was unknown; a genome-wide imaging screen showed its loss enhances STING signaling and that it clusters with the retrograde transport factor USE1, establishing a candidate function in Golgi-to-ER transport that restrains STING.

   Evidence Genome-wide optical pooled CRISPR screen with high-content subcellular imaging of STING localization in 45 million cells, phenotypic clustering, and functional validation of STING signaling upon gene loss

   PMID:38645119 PMID:39657680

   Open questions at the time

   • No direct physical interaction between C19orf25 and USE1 or other transport machinery demonstrated
   • No in vitro reconstitution or biochemical assay defining a molecular activity
   • Mechanism by which the implicated transport pathway restrains STING not resolved

• The molecular activity, direct binding partners, and subcellular localization of C19orf25, and the precise mechanism linking it to Golgi-to-ER transport and STING regulation, remain undefined.
• No structural or biochemical characterization
• No confirmed localization data
• No reciprocal validation of the USE1 association