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Crbn modulates calcium influx by regulating Orai1 during efferocytosis

Author

Listed:
  • Hyunji Moon

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Chanhyuk Min

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Gayoung Kim

    (Gwangju Institute of Science and Technology)

  • Deokhwan Kim

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Kwanhyeong Kim

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Sang-Ah Lee

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Byeongjin Moon

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Susumin Yang

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Juyeon Lee

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Seung-Joo Yang

    (Gwangju Institute of Science and Technology)

  • Steve K. Cho

    (Gwangju Institute of Science and Technology)

  • Gwangrog Lee

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Chang Sup Lee

    (Gyeongsang National University)

  • Chul-Seung Park

    (Gwangju Institute of Science and Technology)

  • Daeho Park

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology
    Ewha Womans University)

Abstract

Calcium flux regulating intracellular calcium levels is essential and modulated for efficient efferocytosis. However, the molecular mechanism by which calcium flux is modulated during efferocytosis remains elusive. Here, we report that Orai1, a Crbn substrate, is upregulated via its attenuated interaction with Crbn during efferocytosis, which increases calcium influx into phagocytes and thereby promotes efferocytosis. We found that Crbn deficiency promoted phagocytosis of apoptotic cells, which resulted from facilitated phagocytic cup closure and was nullified by a CRAC channel inhibitor. In addition, Orai1 associated with Crbn, resulting in ubiquitination and proteasomal degradation of Orai1 and alteration of SOCE-mediated calcium influx. The association of Orai1 with Crbn was attenuated during efferocytosis, leading to reduced ubiquitination of Orai1 and consequently upregulation of Orai1 and calcium influx. Collectively, our study reveals a regulatory mechanism by which calcium influx is modulated by a Crbn-Orai1 axis to facilitate efferocytosis.

Suggested Citation

  • Hyunji Moon & Chanhyuk Min & Gayoung Kim & Deokhwan Kim & Kwanhyeong Kim & Sang-Ah Lee & Byeongjin Moon & Susumin Yang & Juyeon Lee & Seung-Joo Yang & Steve K. Cho & Gwangrog Lee & Chang Sup Lee & Chu, 2020. "Crbn modulates calcium influx by regulating Orai1 during efferocytosis," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19272-0
    DOI: 10.1038/s41467-020-19272-0
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    Cited by:

    1. Jianting Shi & Xun Wu & Ziyi Wang & Fang Li & Yujiao Meng & Rebecca M. Moore & Jian Cui & Chenyi Xue & Katherine R. Croce & Arif Yurdagul & John G. Doench & Wei Li & Konstantinos S. Zarbalis & Ira Tab, 2022. "A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Yuki Fujiwara & Robert J. Torphy & Yi Sun & Emily N. Miller & Felix Ho & Nicholas Borcherding & Tuoqi Wu & Raul M. Torres & Weizhou Zhang & Richard D. Schulick & Yuwen Zhu, 2021. "The GPR171 pathway suppresses T cell activation and limits antitumor immunity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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