Non-structural protein 6: a hallmark of SARS-CoV-2 disease progression and its connection to lipid droplets

The genome of SARS-CoV-2 has been heavily studied with the roles of many enzymatic, and structural proteins being well-defined. However, knowledge remains limited for the 16 non-structural proteins (NSPs) known to be encoded by the genome. Until recently, these NSPs were not considered to be of importance for the viral lifecycle. Recent findings have demonstrated that NSP6 is a key determinant of disease progression. It is a multifunctional protein involved in the stimulation of the formation of double-membrane vesicles (DMVs) from the endoplasmic reticulum (ER), inhibition of autophagosome expansion within the cell, and induction of pyroptosis along with additional functions. In addition, many (+) ssRNA viruses, including SARS-CoV-2, have been shown to manipulate lipid droplets (LDs), highly conserved intracellular organelles that are composed of neutral lipids, as substrates for energy and as platforms for their replication. This article will highlight the current knowledge on NSP6 encoded in the SARS-CoV-2 genome and the involvement of LDs in the SARS-CoV-2 lifecycle, focusing on 1) NSP6 and its integral role as a determinant of viral pathogenicity and 2) the relation of NSP6 with the functionality of LDs in relation to DMVs and SARS-CoV-2 pathogenesis. It is evident that NSP6 is a critical protein to target in order to disrupt the viral life cycle. Thus, understanding the molecular details of the NSPs and their roles in the viral pathway presents an opportunity to identify potential therapeutic targets. Therefore, further investigation into the involvement of NSPs in disease progression is essential for furthering our understanding of the SARS-CoV-2 infection cycle.