Zhang et al.
Secretory pathway and multiple functions of nonstructural protein 1 in flavivirus infection
Front Immunol. 2023;14:1205002. doi:10.3389/fimmu.2023.1205002

The genome of flaviviruses encodes – besides three structural proteins (capsid, premembrane, envelope) – seven non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. These NS proteins mainly participate in viral RNA replication and innate immune evasion.

NS1 is the only NS protein which could be released into extracellular environment. All flavivirus NS1 genes are highly conserved, encoding a polypeptide of 352 amino acids with a molecular weight of 46 to 55 kDa depending on its glycosylation status; TBE virus has three glycosylation sites at positions N23, N85 and N207. During translation, newly synthesized NS1 is translocated into the lumen of endoplasmic reticulum (ER) through a signal sequence of N-terminal 24 amino acids. After dimerization, a certain part is trafficked into the plasma membrane of mammalian cells. Another part is forming hexamers (sNS1) and is secreted into the extracellular environment, and it can also be found in the serum of infected hosts.

Differences exist in the location and the secretory route of NS1 in vertebrate and mosquito cells. Differences also exist in the glycosylation pattern. In insect cells, NS1 is glycosylated only by mannose residues, while it is complex in vertebrate cells.

NS1 is involved in early stages of the replication of RNA, and evidence has demonstrated that NS1 interacts with the structural proteins prM/E within the ER lumen, assists membrane banding and envelopment of nucleocapsids, and eventually mediates the production of infectious virus particles.

High levels of NS1 may be detected in the serum of infected animals and humans (up to 10 mg/ml), and thus it can be used as a diagnostic marker. NS1 can drive complement activation in the presence of antibodies and is involved in the regulation of the complement system. NS1 can trigger endothelial hyperpermeability, resulting in vascular leakage and can contribute to the severity of flavivirus disease. Thus, NS1 has multiple functions in viral replication, immune evasion, pathogenesis, and interaction with the host.

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