Authors
Zhichuan Zhu, Quentin Hahn, Lila E Turbiville, Pengda Liu
Published in
Science signaling. Volume 19. Issue 943. Pages eaef1474. Jun 23, 2026. Epub Jun 23, 2026.
Abstract
The E3 ubiquitin ligase APC/C with its coactivator Cdh1 is generally considered to be a tumor suppressor, regulating genome stability and the G1/S transition of the cell cycle. Cdh1 enhances the stability of immune-cell checkpoint ligand PD-L1 to modulate adaptive immunity. Here, we explored its role in innate immune regulation and identified a noncanonical, degradation-independent function of Cdh1 in clear cell renal cell carcinoma (ccRCC) through its stabilization of the cytosolic double-stranded DNA (dsDNA) sensor STING. Protein levels of Cdh1 and STING were concurrently increased in ccRCC samples from patients, and Cdh1 depletion reduced the abundance and half-life of STING protein in ccRCC cell lines. Mechanistically, Cdh1 bound to the destruction-box degron motif of STING, which sterically prevented the binding of the E3 ubiquitin ligase SPOP, thereby protecting STING from degradation. Upon stimulation of STING with an agonist or dsDNA, Cdh1 bound to STING at the Golgi and increased its abundance and signaling activity. Pharmacologically inhibiting kinases that phosphorylate Cdh1 increased STING abundance and STING-mediated type 1 interferon signaling in ccRCC cells, presumably by promoting the formation of APC/C-Cdh1-STING complexes. These findings reveal a Cdh1-STING axis in ccRCC that might be therapeutically exploited to potentiate antitumor innate immunity.
PMID:
42335217
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.
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