Figure 3.

Mechanisms of inflammasome activation in CoV infection. In the lungs when the S protein of SARS-CoV-2 binds to the ACE2 receptor, the virus is internalized by endocytosis, leading to translation and RNA replication of genomic and sub-genomic RNA including ORF3a, ORF8b, and the viral structural proteins (N, S, M, and E proteins). The E protein is involved in Ca²⁺ release from the Golgi apparatus. This Ca²⁺ has the potential to activate the inflammasome. In addition, ORF3a interacts with TRAF3 to ubiquitinate ASC, and ORF8b interacts with NLRP3, resulting in inflammasome activation and pyroptosis. IL-1β is released through the GSDM-D-N pore during pyroptosis, while Na⁺ and H₂O molecules enter the cell, resulting in cell swelling, which then manifests as pulmonary edema. Furthermore, ORF3a also acts in the cell membrane as a K⁺ channel, which causes an ionic imbalance also capable of promoting inflammasome activation, and mitochondrial dysfunction produces ROS that also contribute to inflammasome activation.