SARS-CoV-2 remodels the Golgi apparatus to facilitate viral assembly and secretion

Abstract

The COVID-19 pandemic is caused by the enveloped virus SARS-CoV-2. Despite o extensive investigation, the molecular mechanisms for its assembly and secretion remain largely elusive. Here, we show that SARS-CoV-2 infection induces global alterations of the host endomembrane system, including dramatic Golgi fragmentation. SARS-CoV-2 virions are enriched in the fragmented Golgi. Blocking endoplasmic reticulum (ER) to Golgi trafficking dramatically inhibits SARS-CoV-2 assembly and secretion without reducing viral genome replication. Significantly, SARS-CoV-2 infection down-regulates GRASP55 but up-regulates TGN46 protein levels. Surprisingly, GRASP55 expression reduces both viral secretion and spike number on each virion without affecting viral entry, while GRASP55 depletion displays opposite effects. In contrast, TGN46 depletion only inhibits viral secretion without affecting spike incorporation into virions. Taken together, we show that SARS-CoV-2 alters Golgi structure and function to modulate viral assembly and secretion, highlighting the Golgi as a potential therapeutic target for blocking SARS-CoV-2 infection. pathway, we provide compelling evidence that the virus instead traffics through the Golgi and relies on the conventional ER-to-Golgi pathway for virion assembly and release. Intriguingly, SARS-CoV-2 infection down-regulates the Golgi stack protein GRASP55 while up-regulating TGN46, a less characterized trans-Golgi network (TGN) protein. Depletion of GRASP55 enhances both spike protein incorporation into virions and viral trafficking, whereas GRASP55 expression has the opposite effect. In contrast, TGN46 depletion inhibits viral trafficking but not assembly, suggesting distinct roles for these proteins at different stages of infection. Collectively, our findings demonstrate that SARS-CoV-2 modulates GRASP55 and TGN46 levels to remodel the Golgi apparatus, facilitating viral assembly and secretion. This mechanism appears conserved across SARS-CoV-2 variants, advancing our understanding of how the virus exploits the host secretory pathway.