The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism

Rattani, A.; Anderson, C.; Trim, W. V.; Garita, E.; Imada, S.; Khawaled, S.; Shin, H.; Zhang, J.; Yilmaz, O. H.; Kirschner, M. W.

doi:10.1101/2025.10.12.681896

bioRxiv · 10.1101/2025.10.12.681896

The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism

Rattani, A.·Anderson, C.·Trim, W. V.·Garita, E.·Imada, S.·Khawaled, S.·Shin, H.·Zhang, J.·Yilmaz, O. H.·Kirschner, M. W.

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Abstract

APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator {beta}-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC-AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Xenopus embryos, mouse colon, and human colorectal cancer cells and restricts SREBP2 target-gene expression, cholesterol synthesis, and tissue cholesterol levels. Mechanistically, APC and AXIN1 promote SREBP2 degradation via a conserved phosphodegron, which marks SREBP2 for ubiquitination by the E3 enzyme, FBXW7. Like {beta}-catenin, SREBP2 is stabilized by extracellular Wnt ligands; unlike {beta}-catenin, its regulation is independent of GSK3{beta} and CK1 and requires the entire APC mutational cluster region (MCR), whereas {beta}-catenin turnover can operate with only a partial MCR. These findings define a {beta}-catenin-independent branch of Wnt signaling that couples APC to sterol metabolism, providing a mechanistic rationale to target the mevalonate/SREBP2 axis in APC-mutant colorectal cancer.

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Rattani, A., Anderson, C., Trim, W. V., Garita, E., Imada, S., Khawaled, S., Shin, H., Zhang, J., Yilmaz, O. H., Kirschner, M. W.. 2025-10-14. The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism. https://doi.org/10.1101/2025.10.12.681896

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