Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

Abstract

The high human cost of Zika virus infections and the rapid establishment of virus circulation in novel areas, including the United States, present an urgent need for countermeasures against this emerging threat. The development of an effective vaccine against Zika virus may be problematic because of the cross reactivity of the antibodies with other flaviviruses leading to antibody-dependent enhancement of infection. Moreover, rapidly replicating positive strand RNA viruses, including Zika virus, generate large spectrum of mutant genomes (quasi species) every replication round, allowing rapid selection of variants resistant to drugs targeting virus-specific proteins. On the other hand, viruses are ultimate cellular parasites and rely on the host metabolism for every step of their life cycle, thus presenting an opportunity to manipulate host processes as an alternative approach to suppress virus replication and spread. Zika and other flaviviruses critically depend on the cellular secretory pathway, which transfers proteins and membranes from the ER through the Golgi to the plasma membrane, for virion assembly, maturation and release. In this review, we summarize the current knowledge of interactions of Zika and similar arthropod-borne flaviviruses with the cellular secretory machinery with a special emphasis on virus-specific changes of the secretory pathway. Identification of the regulatory networks and effector proteins required to accommodate the trafficking of virions, which represent a highly unusual cargo for the secretory pathway, may open an attractive and virtually untapped reservoir of alternative targets for the development of superior anti-viral drugs.

Keywords: Zika virus; flaviviruses; membrane trafficking; secretory pathway; virion maturation.

Figure 1

Scheme of Zika virus genome. The distribution of individual peptides and cleavage sites relative to the ER membrane are indicated. Cyt—cytoplasmic side, lum, -luminal side, tm—transmembrane. Red triangles designate cleavages performed by the viral protease complex NS2B-NS3 on the cytoplasmic side of the ER; brown triangles indicate cleavages performed by cellular proteases inside the ER lumen; green star shows final maturation cleavage of M glycoprotein performed by the Golgi-resident protease furin.

Figure 2

Compartments of the secretory pathway. Transport steps are indicated by arrows. Secretory cargos are synthesized in the ribosome-studded ER, exit the ER at ERES in COPII-coated (brown) vesicles and are transported to the ER-Golgi compartment (ERGIC) and then to the Golgi. After passage through the Golgi complex in the cis-to-trans direction, cargos are packaged at the TGN for delivery to the PM, early and late endosomes and in some cells to secretory granules. Sorting into endosomal compartments and secretory granules is mediated by clathrin-coated (red) vesicles. Transport to the PM is mediated by transport tubules. A COPI-mediated (green) recycling pathway retrieves escaped proteins from the ERGIC and the Golgi and returns them to the ER. Multivesicular bodies form by invaginations of endosomal membrane into its lumen and can fuse with the PM to release their content of exosomal vesicles.

Figure 3

Possible Zika virion secretion pathways. Immature virions accumulate in the ER-Golgi hybrid compartment where the viral surface glycoproteins undergo final glycosylation and proteolytic maturation. Membrane-wrapped clusters of virions could be secreted through a secretory autophagy-related pathway (pathway 1). Individual virions can be released via a secretory granule-like mechanism after repackaging into individual small membranous carriers (pathway 2), which seems to be the major mechanism of virion egress. Virion clusters could be released via direct fusion of the large membranous compartments with the PM (pathway 3).