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bioRxiv · 10.64898/2026.03.25.714063

Nup358 Sustains Intestinal Epithelial Homeostasis by Preventing Dvl1 Condensate Formation to Restrain Wnt Signaling

D'Angelo, M.·Guglielmi, V.·Sakuma, S.·Zhu, E. Y.·Lam, D.
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Abstract

Nucleoporins are increasingly recognized as tissue-specific regulators beyond their structural roles in the nuclear pore complex. Here, we identify nucleoporin Nup358 as a critical repressor of Wnt signaling required for intestinal epithelium integrity. Ablation of Nup358 in adult mice causes a catastrophic loss of crypt-villus architecture and disrupts the intestinal epithelial layer. Notably, while the intestinal stem cell (ISC) pool remains stable, the transit-amplifying (TA) progenitor compartment is depleted. Mechanistically, we show that the interaction of Nup358 with Dvl1 through its N-terminal domain inhibits Dvl1 spontaneous phase separation. In the absence of Nup358, Dvl1 biomolecular condensates promote Tankyrase-mediated degradation of Axin1, leading to the constitutive stabilization of {beta}-catenin and ligand-independent Wnt activation, negatively impacting cell differentiation and TA progenitor survival. Our results demonstrate that Nup358 acts as a molecular safeguard that dampens Wnt signaling levels in intestinal crypts. By preventing Dvl1-mediated Wnt signal amplification, Nup358 allows ISCs to transition into the TA compartment and initiate the differentiation programs essential for intestinal homeostasis.

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D'Angelo, M., Guglielmi, V., Sakuma, S., Zhu, E. Y., Lam, D.. 2026-03-26. Nup358 Sustains Intestinal Epithelial Homeostasis by Preventing Dvl1 Condensate Formation to Restrain Wnt Signaling. https://doi.org/10.64898/2026.03.25.714063

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