ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

Beibei Wu; Arunachalam Ramaiah; Gustavo Garcia Jr.; Yousang Gwack; Vaithilingaraja Arumugaswami; Sonal Srikanth

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ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

Beibei Wu; Arunachalam Ramaiah; Gustavo Garcia Jr.; Yousang Gwack; Vaithilingaraja Arumugaswami; Sonal Srikanth.

Afiliación

Beibei Wu; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Arunachalam Ramaiah; Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697, USA
Gustavo Garcia Jr.; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Yousang Gwack; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Vaithilingaraja Arumugaswami; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Sonal Srikanth; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-442548

ABSTRACT

ABSTRACT

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.

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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2021 Tipo del documento: Preprint

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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2021 Tipo del documento: Preprint