A molecular sensor to characterize arenavirus envelope glycoprotein cleavage by subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P).

Oppliger J1, da Palma JR1, Burri DJ2, Bergeron E3, Khatib AM4, Spiropoulou CF3, Pasquato A5, Kunz S5.

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Abstract

Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses only genetic information is available and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears therefore as a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate efficiency and subcellular location of arenavirus GPC processing. In proof-of-concept, our sensor correctly predicts efficient processing of the GPC of the newly emerged pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and non-pathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system to assess processing of putative cleavage sites derived from newly discovered arenavirus GPC by SKI-1/S1P of humans or any other species, based solely on sequence information.

IMPORTANCE:

Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive infection of arenaviruses in human cells is processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). In order to break the species barrier during zoonotic transmission and to cause severe disease in man, newly emerging arenaviruses must be able to efficiently hijack human SKI-1/S1P. Here we implement a newly developed cell-based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emerged pathogenic Lujo virus by human SKI-1/S1P. Our sensor represents thus a rapid and robust test system to assess if the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information.