hCINAP regulates the differentiation of embryonic stem cells by regulating NEDD4 liquid-liquid phase-separation-mediated YAP1 activation
Ruipeng Zhuge,
Chao Wang,
Jie Wang,
Shuyu Yu,
Liming Liao,
Xiaofeng Zheng
Affiliations
Ruipeng Zhuge
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Chao Wang
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Jie Wang
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Shuyu Yu
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Liming Liao
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Xiaofeng Zheng
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China; Corresponding author
Summary: YAP1 functions in lineage differentiation of pluripotent embryonic stem cells (ESCs); however, the detailed mechanisms underlying the regulation of YAP1 activity during ESC differentiation remain elusive. Here, we report that hCINAP serves as a negative regulator of YAP1 during ESC fate decisions. The expression of mCINAP, the murine homolog of hCINAP, is downregulated during the differentiation process of murine ESC (mESC) ectoderm lineage, leading to liquid-liquid phase separation (LLPS) of NEDD4 and activation of YAP1. Mechanistically, hCINAP interacts with and prevents NEDD4 from forming cytoplasmic condensates that compartmentalize YAP1 and its kinase NLK, facilitating YAP1 phosphorylation at Ser128 and promoting YAP1 activation. mCINAP depletion leads to the formation of NEDD4 condensates and YAP1 activation, which impedes endoderm differentiation of mESCs. Our study shows that hCINAP is a vital regulator of YAP1 activity and is essential for stem cell fate decisions, which provides mechanistic insight into early embryogenesis.
