Smohaze-Upregulated RFWD3 Competes with TRIM24 to Stabilize TREX1 and Reduce Cytosolic dsDNA in Non-Small Cell Lung Cancer.

ABSTRACT: The three-prime repair exonuclease 1 (TREX1), an intracellular double-stranded DNA (dsDNA) degrader that inhibits the stimulator of interferon (IFN) genes (STING) pathway, is turned over by E3 ligase TRIM24-mediated proteasomal degradation. To uncover TREX1-stabilizers in non-small cell lung cancer (NSCLC), mass spectrometry is conducted, and 374 candidates are identified, with the RING Finger and WD Repeat Domain 3 (RFWD3) as a TREX1 protector that sequesters it from TRIM24. Overexpression of RFWD3 promotes tumor growth with increased myeloid-derived suppressor cells (MDSCs), while inhibition of RFWD3 increases intracellular dsDNA levels, activates the STING-IFN signaling, decreases MDSCs, and enhances the efficacy of PD-L1 blockade in murine NSCLC models. Furthermore, smoker patients hav

SUBMITTER: Shi XY 

PROVIDER: S-EPMC12752551 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature