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

Zhe Ji, Wing-Yan Skyla Siu, Maria Emilia Dueñas, Leonie Müller, Matthias Trost and Pedro Carvalho ()
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Zhe Ji: University of Oxford
Wing-Yan Skyla Siu: University of Oxford
Maria Emilia Dueñas: Newcastle University
Leonie Müller: Newcastle University
Matthias Trost: Newcastle University
Pedro Carvalho: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58681-x

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