Fig. 4.

Putative role of Gsk-3 in the SARS-CoV-2 replication and COVID-19 pathogenesis.

Activated Gsk-3 phosphorylate the nucleocapsid protein of SARS-CoV-2 and support viral genome replication and transcription. Simultaneously, activated Gsk-3 also phosphorylate and degrade the significant oxidative stress combating transcription factor Nrf2, resulting outburst of different reactive oxygen species. Circulating DAMPs and PAMPs bind with TLR4 and stimulate the pro-inflammatory cytokine synthesis via Myd88 dependent pathway. β-catenin is a downstream protein of Gsk-3, phosphorylate the p50 sub-unit of NfκB, altered their DNA binding ability, and suppresses inflammatory events. CREB is another transcription factor that initiates the expression of anti-inflammatory genes to overcome the disease condition. During virus infection, activate Gsk-3 degrade the β-catenin protein and phosphorylate the CREB, consequential, lost CBP binding site, and enhances pro-inflammatory cytokine synthesis, especially IL-6. LiCl and Tideglusib are the two well-known non-selective metal cation and non - ATP competitive inhibitors of Gsk-3.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; N-protein: Nucleocapsid protein; sgmRNA: Subgenomic messenger RNA; DAMPs: Death- associated molecular pattern; oxPls: Oxidized phospholipids; TLR: Toll like receptor; Gsk-3: Glycogen synthase kinase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid 2–related factor 2; Cul3: Cullin 3; CREB: cAMP response element-binding protein; CBP: CREB binding proteins; ARE: Antioxidant Response Element References; Myd88: Myeloid differentiation factor 88; IRAKs: Interleukin (IL)- 1R-associated kinase; TRAF6: Tumour necrosis factor receptor associated factor 6; TAK1: Transforming growth factor-β (TGF-β)-activated kinase 1; IκB: Inhibitor of kappa B; TIRAP: TIR-domain-containing adaptor protein; LiCl: Lithium chloride.