CryoEM structures of the multimeric secreted NS1, a major factor for dengue hemorrhagic fever

Abstract

Dengue virus infection can cause dengue hemorrhagic fever (DHF). Dengue NS1 is multifunctional: the intracellular dimeric NS1 (iNS1) forms part of the viral replication complex, the extracellular multi-oligomeric secreted NS1 (sNS1) is a major factor contributing to DHF. The structure of the iNS1 is well studied but not sNS1. Here we show the tetrameric (stable and loose conformation) and hexameric structures of sNS1. Stability of the stable and loose tetramers is determined by the conformation of their N-terminal domain – elongated β- sheet or β-roll. Binding of an anti-NS1 Fab breaks the loose tetrameric and hexameric sNS1 into dimers, whereas the stable tetramer remains largely unbound. Our results show detailed quaternary organization of different oligomeric states of sNS1 and will contribute towards the design of dengue therapeutics.

Structural dynamics of Zika virus NS1 via a reductionist approach reveal the disordered nature of its β-roll domain in isolation

“…27 Recently, a report has shown how the structural flexibility of β-roll domain of DENV NS1 may determine the loose teramer or stable tetramer formation of the secretory NS1. 28 As per our observations, β-roll domain of ZIKV is disordered in isolation. Significant structural changes in the presence of membrane mimetics and membrane co-solvent mimetics is not observed.…”

The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection

“…Dimeric, intracellular NS1 associates with the lumen of the endoplasmic reticulum and participates in the formation of the viral replication complex [ 8 – 10 ]. NS1 is also secreted from infected cells as a tetramer and/or hexamer, with NS1 dimers oligomerizing around a lipid cargo enriched in triglycerides, cholesteryl esters and phospholipids [ 7 , 11 , 12 ]. Secreted NS1 plays multiple roles during infection, including binding and inactivating complement components and interacting directly with endothelial cells to induce endothelial hyperpermeability and pathogenic vascular leak [ 13 – 17 ].…”

Soluble NS1 Antagonizes IgG- and IgA- Mediated Monocytic Phagocytosis of DENV Infected Cells

“…Initially synthesized as a monomer, intracellular NS1 (iNS1) rapidly forms a membrane-associated homodimer in the ER and serves as core component of the viral replication complex (15,16). Dimeric NS1 can also be found on the membrane of infected cells (mNS1) (17)(18)(19)(20), and is secreted by infected cells into the extracellular space in higher-order oligomeric forms (21,22). Once in circulation, secreted NS1 (sNS1) is thought to be a mechanistic trigger of vascular leakage symptoms in DHF/DSS by binding and destabilizing vascular endothelial cells and by activating the innate immune system through direct engagement of toll-like receptors (23,24).…”