Tick-borne encephalitis virus capsid protein induces translational shutoff as revealed by its structural-biological analysis

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Publikace nespadá pod Fakultu sportovních studií, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.
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SELINGER Martin NOVOTNY Radim SYS Jakub ROBY Justin A TYKALOVA Hana GANJI Sri Ranjani VANCOVA Marie JAKLOVA Katerina KAUFMAN Filip BLOOM Marshall E ZDRÁHAL Zbyněk GRUBHOFFER Libor FORWOOD Jade K HRABAL Richard RUMLOVA Michaela STERBA Jan

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj JOURNAL OF BIOLOGICAL CHEMISTRY
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.sciencedirect.com/science/article/pii/S0021925822010286?via%3Dihub
Doi http://dx.doi.org/10.1016/j.jbc.2022.102585
Klíčová slova Capsid; Capsid Proteins; Encephalitis Viruses; Tick-Borne; RNA; Viral Nonstructural Proteins
Popis Tick-borne encephalitis virus (TBEV) is the most medically relevant tick-transmitted Flavivirus in Eurasia, targeting the host central nervous system and frequently causing severe encephalitis. The primary function of its capsid protein (TBEVC) is to recruit the viral RNA and form a nucleocapsid. Additional functionality of Flavivirus capsid proteins has been documented, but further investigation is needed for TBEVC. Here, we show the first capsid protein 3D structure of a member of the tick-borne flaviviruses group. The structure of monomeric ?16-TBEVC was determined using high-resolution multidimensional NMR spectroscopy. Based on natural in vitro TBEVC homodimerization, the dimeric interfaces were identified by hydrogen deuterium exchange mass spectrometry (MS). Although the assembly of flaviviruses occurs in endoplasmic reticulum–derived vesicles, we observed that TBEVC protein also accumulated in the nuclei and nucleoli of infected cells. In addition, the predicted bipartite nuclear localization sequence in the TBEVC C-terminal part was confirmed experimentally, and we described the interface between TBEVC bipartite nuclear localization sequence and import adapter protein importin-alpha using X-ray crystallography. Furthermore, our coimmunoprecipitation coupled with MS identification revealed 214 interaction partners of TBEVC, including viral envelope and nonstructural NS5 proteins and a wide variety of host proteins involved mainly in rRNA processing and translation initiation. Metabolic labeling experiments further confirmed that TBEVC and other flaviviral capsid proteins are able to induce translational shutoff and decrease of 18S rRNA. These findings may substantially help to design a targeted therapy against TBEV.
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