The dorsoventral gradient of BMP signaling plays an essential role in embryonic patterning. Zinc Finger SWIM-Type Containing 4 (zswim4) is expressed in the Spemann-Mangold organizer at the onset of Xenopus gastrulation and is then enriched in the developing neuroectoderm at the mid-gastrula stages. Knockdown or knockout of zswim4 causes ventralization. Overexpression of zswim4 decreases, whereas knockdown of zswim4 increases the expression levels of ventrolateral mesoderm marker genes. Mechanistically, ZSWIM4 attenuates the BMP signal by reducing the protein stability of SMAD1 in the nucleus. Stable isotope labeling by amino acids in cell culture (SILAC) identifies Elongin B (ELOB) and Elongin C (ELOC) as the interaction partners of ZSWIM4. Accordingly, ZSWIM4 forms a complex with the Cul2-RING ubiquitin ligase and ELOB and ELOC, promoting the ubiquitination and degradation of SMAD1 in the nucleus. Our study identifies a novel mechanism that restricts BMP signaling in the nucleus.

Zswim4 fine-tunes BMP signaling in Xenopus early embryonic patterning by interacting with the Cul2-RING ubiquitin ligase, Elongin B and C, thereby forming a protein disruption complex that ultimately reduces nuclear Smad1 protein stability.Zswim4 is a novel inhibitor of the BMP signaling pathway, localized in the nucleus. Zswim4 physically interacts with Smad1 through the Smad1 MH1 domain. Zswim4 reduces Smad1 stability and increases Smad1 ubiquitination in the nucleus. Zswim4 interacts with Cullin2 and Elongin B and C, forming a protein disruption complex to promote Smad1 ubiquitination.

Zswim4 fine-tunes BMP signaling in Xenopus early embryonic patterning by interacting with the Cul2-RING ubiquitin ligase, Elongin B and C, thereby forming a protein disruption complex that ultimately reduces nuclear Smad1 protein stability.