Shaping the flavivirus replication complex: It is curvaceous!

Abstract

Flavivirus replication is intimately involved with remodelled membrane organelles that are compartmentalised for different functions during their life cycle. Recent advances in lipid analyses and gene depletion have identified a number of host components that enable efficient virus replication in infected cells. Here, we describe the current understanding on the role and contribution of host lipids and membrane bending proteins to flavivirus replication, with a particular focus on the components that bend and shape the membrane bilayer to induce the flavivirus-induced organelles characteristic of infection.

Keywords: flavivirus replication; lipids; membrane curvature; replication complex.

Figure 1

Hypothetical model for the flavivirus replication complex (RC); vesicle packet (VP). Flavivirus infection constructs membrane proliferations termed VPs which house the viral RC. The construction and stability of the RC promotes an exponential increase in viral replication. Translation of viral proteins on the surface of the ER acts as a platform for protein–protein and protein–lipid interactions. Viral proteins interact with DNAJC14, which acts as a chaperone to modulate VP formation (Yi et al., 2011, Yi et al., 2012), potentially on cholesterol‐rich microdomains (Mackenzie et al., 2007). We speculate that the viral protein NS4A (based on its predicted topology, structure, and membrane remodelling capacity [Roosendaal et al., 2006, Miller et al., 2007]) induces membrane curvature while interacting with the host RTN3.1A protein (Aktepe et al., 2017). We suggest that the biogenesis and recruitment of the cone‐shaped lipids ceramide (Aktepe et al., 2015) and lyso‐PChol (Liebscher et al., 2018) stabilises and provides the required curvature for the formation of the VP. Viral and host proteins supporting the VP neck structure (an integral component of the VP that allows for the passage of nucleotides, proteins, and viral RNA) is currently unknown; however, components of the ESCRT complex may be recruited to aid in the stabilisation of the neck (Barajas et al., 2009, Barajas et al., 2014, Diaz et al., 2015)