RT Journal Article
SR Electronic
T1 ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.04.442548
DO 10.1101/2021.05.04.442548
A1 Beibei Wu
A1 Arunachalam Ramaiah
A1 Gustavo Garcia, Jr.
A1 Yousang Gwack
A1 Vaithilingaraja Arumugaswami
A1 Sonal Srikanth
YR 2021
UL http://biorxiv.org/content/early/2021/05/04/2021.05.04.442548.abstract
AB ORAI1 and STIM1 are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of a cytosolic nucleic acid sensing pathway. Using ORAI1 and STIM1 knockout cells, we examined their contribution to the host response to SARS-CoV-2 infection. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection due to enhanced type I interferon response. On the contrary, ORAI1 knockout cells showed high susceptibility to SARS-CoV-2 infection as judged by increased expression of viral proteins and a high viral load. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic interferon signaling. Transcriptome analysis showed downregulation of multiple cellular defense mechanisms, including antiviral signaling pathways in ORAI1 knockout cells, which are likely due to reduced expression of the Ca2+-dependent transcription factors of the activator protein 1 (AP-1) family and MEF2C. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the baseline type I interferon level, which is a determinant of host resistance to SARS-CoV-2 infection.Competing Interest StatementThe authors have declared no competing interest.