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The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators

Author

Listed:
  • Rong-Gui Hu

    (California Institute of Technology)

  • Jun Sheng

    (California Institute of Technology)

  • Xin Qi

    (California Institute of Technology)

  • Zhenming Xu

    (California Institute of Technology
    University of California)

  • Terry T. Takahashi

    (California Institute of Technology)

  • Alexander Varshavsky

    (California Institute of Technology)

Abstract

The conjugation of arginine to proteins is a part of the N-end rule pathway of protein degradation. Three amino (N)-terminal residues—aspartate, glutamate and cysteine—are arginylated by ATE1-encoded arginyl-transferases. Here we report that oxidation of N-terminal cysteine is essential for its arginylation. The in vivo oxidation of N-terminal cysteine, before its arginylation, is shown to require nitric oxide. We reconstituted this process in vitro as well. The levels of regulatory proteins bearing N-terminal cysteine, such as RGS4, RGS5 and RGS16, are greatly increased in mouse ATE1-/- embryos, which lack arginylation. Stabilization of these proteins, the first physiological substrates of mammalian N-end rule pathway, may underlie cardiovascular defects in ATE1-/- embryos. Our findings identify the N-end rule pathway as a new nitric oxide sensor that functions through its ability to destroy specific regulatory proteins bearing N-terminal cysteine, at rates controlled by nitric oxide and apparently by oxygen as well.

Suggested Citation

  • Rong-Gui Hu & Jun Sheng & Xin Qi & Zhenming Xu & Terry T. Takahashi & Alexander Varshavsky, 2005. "The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators," Nature, Nature, vol. 437(7061), pages 981-986, October.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7061:d:10.1038_nature04027
    DOI: 10.1038/nature04027
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    Cited by:

    1. Agata Zubrycka & Charlene Dambire & Laura Dalle Carbonare & Gunjan Sharma & Tinne Boeckx & Kamal Swarup & Craig J. Sturrock & Brian S. Atkinson & Ranjan Swarup & Françoise Corbineau & Neil J. Oldham &, 2023. "ERFVII action and modulation through oxygen-sensing in Arabidopsis thaliana," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Sylvia Varland & Rui Duarte Silva & Ine Kjosås & Alexandra Faustino & Annelies Bogaert & Maximilian Billmann & Hadi Boukhatmi & Barbara Kellen & Michael Costanzo & Adrian Drazic & Camilla Osberg & Kat, 2023. "N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    3. Verna Van & Janae B. Brown & Corin R. O’Shea & Hannah Rosenbach & Ijaz Mohamed & Nna-Emeka Ejimogu & Toan S. Bui & Veronika A. Szalai & Kelly N. Chacón & Ingrid Span & Fangliang Zhang & Aaron T. Smith, 2023. "Iron-sulfur clusters are involved in post-translational arginylation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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