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Regulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage

Author

Listed:
  • Arne Praznik

    (National Institute of Chemistry
    University of Ljubljana)

  • Tina Fink

    (National Institute of Chemistry)

  • Nik Franko

    (National Institute of Chemistry)

  • Jan Lonzarić

    (National Institute of Chemistry)

  • Mojca Benčina

    (National Institute of Chemistry
    ENFIST Centre of Excellence)

  • Nina Jerala

    (National Institute of Chemistry
    University of Ljubljana)

  • Tjaša Plaper

    (National Institute of Chemistry
    University of Ljubljana)

  • Samo Roškar

    (National Institute of Chemistry)

  • Roman Jerala

    (National Institute of Chemistry
    ENFIST Centre of Excellence)

Abstract

Secreted proteins, such as hormones or cytokines, are key mediators in multicellular organisms. Response of protein secretion based on transcriptional control is rather slow, as it requires transcription, translation and transport from the endoplasmic reticulum (ER) to the plasma membrane via the conventional protein secretion (CPS) pathway. An alternative regulation to provide faster response would be valuable. Here we present two genetically encoded orthogonal regulatory secretion systems, which rely on the retention of pre-synthesized proteins on the ER membrane (membER, released by a cytosolic protease) or inside the ER lumen (lumER, released by an ER-luminal protease), respectively, and their release by the chemical signal-regulated proteolytic removal of an ER-retention signal, without triggering ER stress due to protein aggregates. Design of orthogonal chemically-regulated split proteases enables the combination of signals into logic functions. Its application was demonstrated on a chemically regulated therapeutic protein secretion and regulated membrane translocation of a chimeric antigen receptor (CAR) targeting cancer antigen. Regulation of the ER escape represents a platform for the design of fast-responsive and tightly-controlled modular and scalable protein secretion system for mammalian cells.

Suggested Citation

  • Arne Praznik & Tina Fink & Nik Franko & Jan Lonzarić & Mojca Benčina & Nina Jerala & Tjaša Plaper & Samo Roškar & Roman Jerala, 2022. "Regulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28971-9
    DOI: 10.1038/s41467-022-28971-9
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    References listed on IDEAS

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    1. Daichi Kamiyama & Sayaka Sekine & Benjamin Barsi-Rhyne & Jeffrey Hu & Baohui Chen & Luke A. Gilbert & Hiroaki Ishikawa & Manuel D. Leonetti & Wallace F. Marshall & Jonathan S. Weissman & Bo Huang, 2016. "Versatile protein tagging in cells with split fluorescent protein," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    2. Tina Lebar & Urban Bezeljak & Anja Golob & Miha Jerala & Lucija Kadunc & Boštjan Pirš & Martin Stražar & Dušan Vučko & Uroš Zupančič & Mojca Benčina & Vida Forstnerič & Rok Gaber & Jan Lonzarić & Andr, 2014. "A bistable genetic switch based on designable DNA-binding domains," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
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    1. Anna-Maria Makri Pistikou & Glenn A. O. Cremers & Bryan L. Nathalia & Theodorus J. Meuleman & Bas W. A. Bögels & Bruno V. Eijkens & Anne Dreu & Maarten T. H. Bezembinder & Oscar M. J. A. Stassen & Car, 2023. "Engineering a scalable and orthogonal platform for synthetic communication in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Mohamed Mahameed & Pengli Wang & Shuai Xue & Martin Fussenegger, 2022. "Engineering receptors in the secretory pathway for orthogonal signalling control," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Deqiang Kong & Yang Zhou & Yu Wei & Xinyi Wang & Qin Huang & Xianyun Gao & Hang Wan & Mengyao Liu & Liping Kang & Guiling Yu & Jianli Yin & Ningzi Guan & Haifeng Ye, 2024. "Exploring plant-derived phytochrome chaperone proteins for light-switchable transcriptional regulation in mammals," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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