Figure 1.

Schematic representation of the diverse activities of the SARS-CoV-2 spike (S) protein during infection and syncytia formation. Viral infection begins when the S protein on the surface of the virion interacts with the ACE2 receptor. During early entry, the S protein is processed by the TMPRSS2 protease and fusion occurs on the plasma membrane (PM). The S protein can also fuse with endosomal membranes during late entry, upon being primed by cathepsins and furin. The positive-sense single stranded (+ss) viral genomic RNA is deposited in the cytoplasm and translated. Viral RNA replication and transcription occur on membranes. Upon being transcribed, the S protein is translocated and inserted into the endoplasmic reticulum (ER) and is generally sequestered within intracellular membranes by the membrane structural protein (M). The expression of the S protein leads to intracellular calcium fluctuations and the increased expression of the TMEM16F scramblase. TMEM16F exposes the phosphatidylserine (PS) from the cytofacial leaflet of the PM to the exofacial leaflet. The transcribed S protein is processed by furin and transported throughout the ER-Golgi network. During COPI (retrograde) and COPII (anterograde) transport, leakage of the S protein can occur from vesicles (not shown in simplified schematic). The S protein is then translocated to the PM, where it associates with cholesterols, and induces syncytia formation by interacting with receptors on neighbouring uninfected cells. The sequestered S protein is in packaged into virions that bud into the Golgi or ER-Golgi intermediate compartment (ERGIC), and virions exit the cell via deacidified lysosome-dependent exocytosis (not shown). The ER, ERGIC, and Golgi membranes are bilayers which are represented as single lines in this schematic.