The Role of Human Selenoprotein S in SARS‐CoV‐2 Replication

COVID‐19, caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), spread quickly all over the world and caused a pandemic that urged the scientific community to study the virus. Selenoprotein S is an endoplasmic reticulum (ER) membrane associated selenoprotein that is involved in protein degradation and NFκβ signaling. It also contributes to reducing proinflammatory cytokines TNF‐α, IL‐1β and IL‐6. Selenoprotein S is known to interact with SARS‐CoV‐2 non‐structural protein (nsp7), which is part of the virus replication machine. However, it is not clear whether they interact directly and whether selenoprotein S can still bind nsp7 once it is in complex with the virus’ replication machinery. The role of selenoprotein S in the replication complex is unknown. We used biochemical assays to investigate these open questions and to identify which segment of selenoprotein S is involved in the interaction and which segment is free to recruit other human or viral proteins. We show that selenoprotein S binds tightly and directly to nsp7. Selenoprotein S is a membrane protein and its hydrophobic region is the main segment involved in binding nsp7. The soluble cytosolic segment cannot bind to nsp7. Therefore, it is free for binding to other protein partners. In addition, selenoprotein S was able to bind the nsp7 and nsp8 complex suggesting that it can bind the core replication complex directly. Thus, we suggest that selenoprotein S is a component of the virus core replication complex and may be responsible for recruiting other human proteins to the replication complex.