Crbn modulates calcium influx by regulating Orai1 during efferocytosis

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, Chul-Seung Park and Daeho Park ()
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Hyunji Moon: Gwangju Institute of Science and Technology
Chanhyuk Min: Gwangju Institute of Science and Technology
Gayoung Kim: Gwangju Institute of Science and Technology
Deokhwan Kim: Gwangju Institute of Science and Technology
Kwanhyeong Kim: Gwangju Institute of Science and Technology
Sang-Ah Lee: Gwangju Institute of Science and Technology
Byeongjin Moon: Gwangju Institute of Science and Technology
Susumin Yang: Gwangju Institute of Science and Technology
Juyeon Lee: 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
Chang Sup Lee: Gyeongsang National University
Chul-Seung Park: Gwangju Institute of Science and Technology
Daeho Park: Gwangju Institute of Science and Technology

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19272-0

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