ZSWIM4 regulates embryonic patterning and BMP signaling by promoting nuclear Smad1 degradation

作者：Chengdong Wang, Ziran Liu, Yelin Zeng, Liangji Zhou, Qi Long, Imtiaz Ul Hassan, Yuanliang Zhang, Xufeng Qi, Dongqing Cai, Bingyu Mao, Gang Lü, Jianmin Sun, Yong‐Gang Yao, Yi Deng, Qian Zhao, Bo Feng, Qin Zhou, Wai‐Yee Chan, Hui Zhao · 发表于：EMBO Reports · 年份：2024 · DOI：10.1038/s44319-023-00046-w · 被引用次数：6 · 研究领域：Epigenetics and DNA Methylation、Renal and related cancers、Developmental Biology and Gene Regulation

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.