SARS-CoV-2 lysosomal egress pathway

The early stages of the SARS-CoV-2 lifecycle have been relatively well-defined. However, knowledge of how newly assembled SARS-CoV-2 particles egress from cells remains limited. Until recently, SARS-CoV-2 egress was misunderstood as being dependent on the biosynthetic secretory pathway commonly used by enveloped viruses. Recent findings have demonstrated that SARS-CoV-2 instead utilizes an unconventional lysosomal egress pathway. This pathway has been characterized as being dependent on the Arl8b GTPase for anterograde movement of the lysosome along microtubules to the plasma membrane. Viral hijacking of the lysosomal pathway leads to lysosome deacidification and deactivation of lysosomal hydrolases, which perturbs antigen presentation. However, many questions regarding the molecular details of this lysosome-mediated egress remain unanswered. This article will highlight the current knowledge gaps in the lysosomal-egress pathway, focusing on 1) how newly assembled SARS- CoV-2 particles are trafficked to lysosomes, 2) the mechanisms by which lysosome deacidification occurs, and 3) the reasons why deacidification of lysosomes is essential for successful egress. Through its disruption of lysosome function and perturbation of antigen presentation, the lysosomal egress pathway has implications for the clinical presentation of COVID-19. Furthermore, understanding the molecular details of the pathway presents an opportunity to develop novel therapeutic targets. Therefore, further investigation of the viral and host factors involved in this egress pathway is essential in understanding SARS-CoV-2 as a whole.