Excess phosphate promotes SARSCoV2 N proteininduced NLRP3 inflammasome activation via the SCAPSREBP2 signaling pathway.
Mol Med Rep
; 29(3)2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38275129
ABSTRACT
Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection can promote cardiovascular adverse events in patients with chronic kidney disease. Hyperphosphatemia is associated with elevated inflammation and sterol regulatory element binding protein 2 (SREBP2) activation, but the underlying mechanisms in SARSCoV2 that are related to cardiovascular disease remain unclear. The present study aimed to elucidate the role of excess inorganic phosphate (PI) in SARSCoV2 N proteininduced NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). The expression levels of SARSCoV2 N protein, SREBP cleavageactivating protein (SCAP), mature Nterminal SREBP2, NLRP3, procaspase1, cleaved caspase1, IL1ß and IL18 were examined by western blotting. The expression levels of SREBP2, HMGCoA reductase, HMGCS1, low density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), SREBP1c, fatty acid synthase, stearyl coenzyme A desaturase 1, acetylCoA carboxylase α and ATPcitrate lyase were determined by reverse transcriptionquantitative PCR. The translocation of SCAP or NLRP3 from the endoplasmic reticulum to the Golgi was detected by confocal microscopy. The results showed that excess PI promoted SCAPSREBP and NLRP3 complex translocation to the Golgi, potentially leading to NLRP3 inflammasome activation and lipogenic gene expression. Furthermore, PI amplified SARSCoV2 N proteininduced inflammation via the SCAPSREBP pathway, which facilitates NLRP3 inï¬ammasome assembly and activation. Inhibition of phosphate uptake with phosphonoformate sodium alleviated NLRP3 inflammasome activation and reduced SREBPmediated lipogenic gene expression in VSMCs stimulated with PI and with SARSCoV2 N protein overexpression. Inhibition of SREBP2 or small interfering RNAinduced silencing of SREBP2 effectively suppressed the effect of PI and SARSCoV2 N protein on NLRP3 inflammasome activation and lipogenic gene expression. In conclusion, the present study identified that PI amplified SARSCoV2 N proteininduced NLRP3 inflammasome activation and lipogenic gene expression via the SCAPSREBP signaling pathway.
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Base de datos:
MEDLINE
Asunto principal:
Péptidos y Proteínas de Señalización Intracelular
/
Hiperfosfatemia
/
COVID-19
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Mol Med Rep
Año:
2024
Tipo del documento:
Article