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Phosphorylation-coupled autoregulation of TANGO1 and Sec16A maintains functional ER exit sites

Author

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  • Miharu Maeda

    (Graduate School of Medicine, Department of Biological Informatics and Experimental Therapeutics)

  • Masashi Arakawa

    (Graduate School of Medicine, Department of Biological Informatics and Experimental Therapeutics)

  • Masaki Wakabayashi

    (National Cerebral and Cardiovascular Center, Omics Research Center)

  • Yukie Komatsu

    (Graduate School of Medicine, Department of Biological Informatics and Experimental Therapeutics)

  • Kota Saito

    (Graduate School of Medicine, Department of Biological Informatics and Experimental Therapeutics)

Abstract

Secretory proteins are synthesized in the endoplasmic reticulum (ER) and begin their transport from specialized domains on the ER called ER exit sites (ERES), where COPII proteins assemble. We previously demonstrated that the interaction between TANGO1 and Sec16A is critical for ERES formation. In this study, we reveal that the phosphorylation of TANGO1 and Sec16A is regulated by a FAM83A/CK1α-mediated negative feedback loop. Conversely, their dephosphorylation is regulated in a spatially distinct manner by different phosphatase complexes: PPP6R3/PPP6C for Sec16A and PPP1R15B/PPP1C for TANGO1. Excessive phosphorylation of either TANGO1 or Sec16A leads to ERES disassembly, while excessive dephosphorylation impairs secretion. Our findings demonstrate that maintaining a balanced phosphorylation state of TANGO1 and Sec16A through autoregulation by FAM83A/CK1α and the phosphatases PP1 and PP6 is essential for sustaining proper secretory activity at the ERES.

Suggested Citation

  • Miharu Maeda & Masashi Arakawa & Masaki Wakabayashi & Yukie Komatsu & Kota Saito, 2025. "Phosphorylation-coupled autoregulation of TANGO1 and Sec16A maintains functional ER exit sites," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65409-4
    DOI: 10.1038/s41467-025-65409-4
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