Assembling an understanding: the critical role of SARS-CoV-2 envelope and membrane proteins in virion formation

In March 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a global pandemic. Since then, COVID-19 has claimed the lives of over 2 million people and is continuing to spread at an alarming rate, straining public health systems and crippling economies. The virus responsible for such global devastation is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus (ß-CoV) composed of a positive-sense, single stranded RNA genome surrounded by a viral envelope. The envelope of ß-CoVs consists of four major structural proteins: the envelope (E) protein, membrane (M) protein, spike (S) protein, and nucleocapsid (N) protein, with previous research implicating these proteins in the assembly and budding process of new virion particles. As these structural proteins are relatively conserved, previously acquired knowledge from other ß-CoV strains has helped characterize the structure and function of these viral envelope proteins in the context of SARS-CoV-2. However, our understanding remains incomplete surrounding the SARS-CoV-2 viral assembly and budding process and the host and viral proteins that are involved. This review will summarize the current knowledge on SARS-CoV-2 virion assembly and budding at the endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC). Specifically, the structure of the major viral envelope proteins, E and M, and the conservation of their sequences will be discussed in detail, followed by a thorough examination of the functions of the E and M proteins during viral assembly at the ERGIC. Finally, an in-depth explanation of how these viral envelope proteins not only represent new target molecules for the development of novel therapeutics but also their potential as vaccine candidates will be highlighted. With the emergence of new variants exacerbating the state of the pandemic, advancing our understanding of viral and host proteins involved in the critical steps of the SARS-CoV-2 virus lifecycle remains a crucial aspect in continuing the fight against COVID-19. Expanding global knowledge on the molecular mechanisms of SARS-CoV-2 will provide further insight into the pathogenesis and epidemiology of SARS-CoV-2 infection and create new avenues for vaccine development and therapeutic interventions.