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<p>Cytokines of the TGF-β superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determine how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We show that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1-NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis reveals that MAN1 binds independently to the CTDNEP1-NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex causes nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1-NEP1R1 as the R-SMAD phosphatase, reveal the mechanistic basis for TGF-β signaling inactivation and highlight how this process is disrupted by disease-associated MAN1 mutations.</p>

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Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Zhe Ji,
  • Wing-Yan Skyla Siu,
  • Maria Emilia Dueñas,
  • Leonie Müller,
  • Matthias Trost,
  • Pedro Carvalho

摘要

Cytokines of the TGF-β superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determine how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We show that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1-NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis reveals that MAN1 binds independently to the CTDNEP1-NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex causes nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1-NEP1R1 as the R-SMAD phosphatase, reveal the mechanistic basis for TGF-β signaling inactivation and highlight how this process is disrupted by disease-associated MAN1 mutations.