COVID-19 News: Study Finds That SARS-CoV-2 N Protein Promotes TMAO-Induced NLRP3 Inflammasome Activation Via SCAP-SREBP Signaling Pathway
Nikhil Prasad Fact checked by:Thailand Medical News Team Nov 23, 2023 1 year, 1 month, 5 days, 2 hours, 28 minutes ago
COVID-19 News: In the relentless pursuit of understanding the intricate facets of COVID-19, a recent study conducted at The Affiliated Ganzhou Hospital of Nanchang University in Jiangxi, China, and the Guangzhou Medical University in Guangdong, China, has unearthed a groundbreaking revelation. The research covered in this
COVID-19 News report, explores the interaction between the SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 NP), trimethylamine N-oxide (TMAO), and the inflammatory response in vascular smooth muscle cells (VSMCs).
COVID-19 has been closely associated with inflammation, a key player in severe complications observed in infected patients. Moreover, the virus has been linked to gut dysbiosis, and emerging evidence suggests that elevated TMAO levels from gut microbiota may contribute to chronic low-inflammatory states, impacting the clinical outcomes of COVID-19 patients (Jing et al., 2022). To shed light on the synergistic effects of SARS-CoV-2 and TMAO on inflammation, this study delves into the modulatory effect of SARS-CoV-2 NP on TMAO-induced lipogenesis and NLRP3 inflammasome activation.
Understanding the Molecular Players
Previous studies have identified various proteins associated with inflammation in coronavirus infections. Notably, the SARS-CoV envelope protein and 3a protein were found to activate the NLRP3 inflammasome and interleukin-1β secretion.
Expanding on this, SARS-CoV-2 NP has been implicated in promoting inflammatory cytokine secretion by enhancing NLRP3 inflammasome assembly and activation in macrophages. TMAO, a byproduct of gut microbiota, is known to recruit the NLRP3 inflammasome and trigger inflammatory conditions.
Yet, the intricate molecular mechanisms underlying how SARS-CoV-2 NP facilitates TMAO-induced NLRP3 inflammasome activation remained elusive. The study identifies the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) as a crucial player in this interaction. SREBPs, known regulators of intracellular cholesterol homeostasis, are activated by SCAP, and their dysregulation has been observed in COVID-19 patients. Specifically, SREBP-2 activation was found to induce lipid synthesis and inflammatory activation, highlighting its significance in the context of COVID-19.
The Role of SCAP–SREBP Signaling Pathway
The study elucidates that SARS-CoV-2 NP triggers the dissociation of SCAP from the endoplasmic reticulum, leading to the activation of SREBPs. This activation results in increased expression of lipogenic genes and NLRP3 inflammasome activation. TMAO, on the other hand, facilitates the translocation of the SCAP–SREBP complex from the endoplasmic reticulum to the Golgi apparatus, creating an environment conducive for SARS-CoV-2 NP to directly bind to the NLRP3 protein, thereby promoting NLRP3 inflammasome assembly.
Moreover, the study demonstrates that knockdown of SCAP–SREBP2 effectively mitigates lipogenic gene expression and alleviates NLRP3 inflammasome-mediated systemic inflammation in VSMCs stimulated with TMAO and SARS-CoV-2 NP. These findings underscore the pivotal role of th
e SCAP–SREBP signaling pathway in the amplification of TMAO-induced lipogenesis and NLRP3 inflammasome activation by SARS-CoV-2 NP.
Implications for COVID-19-Related Cardiovascular Disease
Considering the severe cardiovascular dysfunction observed in COVID-19 patients and the higher mortality rate associated with such complications, understanding the role of SARS-CoV-2 in vascular dysfunction becomes paramount. The virus's potential to exploit host lipid metabolism, as evidenced by its interaction with the SCAP–SREBP signaling pathway, raises concerns about its impact on cardiovascular health.
In conclusion, this study not only unravels the molecular intricacies of how SARS-CoV-2 NP amplifies TMAO-induced lipogenesis and NLRP3 inflammasome activation but also identifies the SCAP–SREBP signaling pathway as a potential intervention target for preventing and treating COVID-19-related cardiovascular diseases. As the world continues to grapple with the ongoing pandemic, understanding the nuances of the virus-host interaction at the molecular level is crucial for developing targeted therapeutic strategies and mitigating the severe consequences of COVID-19.
The study findings were published in the peer reviewed journal: Tissue and Cell.
https://www.sciencedirect.com/science/article/abs/pii/S0040816623002641
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