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RNA binding protein, lipids pathways, diacylglycerol and FMRP role in SARS-CoV-2 and fragile X syndrome.

Marcos Altable, Juan Mois?s de la Serna, Emilio D?az-Moreno, Adnan Srifi?Hasnaoui, Alfonso Cruzado

SARS-CoV-2 interacts with ACE2 and infects ACE2-expressing epithelial and endothelial cells in lung and other organs, leading to the down-regulation of ACE2. This induces Ang II accumulation. The interaction of angiotensin II with its G-protein coupled receptor results in the activation of phosphodiesterase phospholipase C. Phospholipase C degrades membrane-bound Phosphatidylinositol 4,5-Bisphosphate (PIP2) to Inositol 1,4, 5-Triphosphate (IP3) and Diacylglycerol (DAG). This results in the release of cytokines and eicosanoids (leukotrienes, prostaglandin, and thromboxane A2). Furthermore, Inositol Triphosphate (IP3)/DAG contribute to Ca2+ release from Endoplasmic Reticulum (ER) increasing intracellular Ca2+ and activating PKC and NF-kB, PI3K/AKT/mTOR and Ras/MAPK/ERK pathways which results in pro-inflammatory cytokines release and regulation of transcription of viral and host proteins. These processes promote a pro-inflammatory and prothrombotic state and cytokine storm. In the absence of Fragile X Retardation Mental Protein (FMRP) as occurs in Fragile X Syndrome (FXS), it has been described an increased DAG levels that lead to the pathologic features of FXS. Then, the absence of FMRP would lead to increased DAG levels, hence elevation of the Ca2+ intracellular, and contribute to damaging effects of DAG in COVID-19. Besides, the inflammasome NLRP3 is involved in the pathogenesis of diseases characterized by an excessive maladaptive inflammatory activation such as acute lung injury and recently described in COVID-19. We showed how inflammasome function is regulated by DAG, as well as DAG increase results in the lack of B cell-T cell communication (immune synapse) and an abnormal antibodies function. Since, relation between DAG and Phosphatidic Acid (PA) is required for optimal B cell function and antibodies production. In COVID-19, DAG/PA activity balance is enhanced, as in FXS. This fact might be involved in impaired antibody developing. It should be noted here that DAG mediates fat-induced insulin resistanc, which has been observed in COVID-19. This article collects for the first time the links between both COVID-19 and FXS, and proposes FXS as a risk factor in COVID-19, as well as COVID-19 could impair FXS symptoms. It described the potential role of described pathways in potential drugs for COVID-19 and FXS treatment