Membrane-Associated Flavivirus Replication Complex—Its Organization and Regulation

Abstract

Flavivirus consists of a large number of arthropod-borne viruses, many of which cause life-threatening diseases in humans. A characteristic feature of flavivirus infection is to induce the rearrangement of intracellular membrane structure in the cytoplasm. This unique membranous structure called replication organelle is considered as a microenvironment that provides factors required for the activity of the flaviviral replication complex. The replication organelle serves as a place to coordinate viral RNA amplification, protein translation, and virion assembly and also to protect the viral replication complex from the cellular immune defense system. In this review, we summarize the current understanding of how the formation and function of membrane-associated flaviviral replication organelle are regulated by cellular factors.

How Viruses Use the VCP/p97 ATPase Molecular Machine

“…Al-though the precise role of NS5A remains unknown, it may serve as a scaffold, much like oxysterol-binding protein (OSBP), to mediate contacts between lipids and proteins [ 91 ]. VCP and its cofactors likely facilitate flaviviral replicase assembly and/or function in the context of ER membranes [ 92 ] ( Figure 2 ).…”

Mosquito-Borne Flaviviruses and Current Therapeutic Advances

“…Therefore, inhibitors targeting NS2B-NS3 could be ideal and attractive therapeutic interventions to combat mosquito-borne flavivirus infections (Figure 1). [6,7]. Most of the current developing antiviral agents against flaviviruses target viral NS3 or NS5 proteins that possess multiple enzymatic activities including the serine protease of NS2B-NS3, the 5′-RNA triphosphatase, the nucleoside triphosphatase (NTPase) and the helicase of NS3, as well as the methyltransferase (Mtase) and the RNA-dependent RNA polymerase (RdRp) of NS5.…”

“…The genome of mosquito-borne flaviviruses is about 11 kb in length and encodes a polyprotein, which is subsequently processed into three structural proteins, i.e., capsid (C), premembrane (prM) or membrane and envelope (E), and seven nonstructural proteins, i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 [5]. The virions bind and enter the host cells through interactions with specific receptors, and viral endocytosis and membrane fusion are triggered to release viral genomes into the cytoplasm for the subsequent replication and translation processes, which involve the participation of various viral NS proteins and host factors [6,7]. Most of the current developing antiviral agents against flaviviruses target viral NS3 or NS5 proteins that possess multiple enzymatic activities including the serine protease of NS2B-NS3, the 5 -RNA triphosphatase, the nucleoside triphosphatase (NTPase) and the helicase of NS3, as well as the methyltransferase (Mtase) and the RNA-dependent RNA polymerase (RdRp) of NS5.…”

How Viruses Use the VCP/p97 ATPase Molecular Machine

“…Although the precise role of NS5A remains unknown, it may serve as a scaffold, much like oxysterol-binding protein (OSBP), to mediate contacts between lipids and proteins [88]. VCP and its cofactors likely facilitate flaviviral replicase assembly and/or function in the context of ER membranes [89] (Figure 2). or BiP pathways.…”