Abstract
Proteolytic processing of flavivirus polyprotein is a uniquely controlled process. To date, the sequential cleavage of the capsid anchor sequence at the junction of C-PrM has been considered essential for the production of flaviviruses. In this study, we used two experimental approaches to show the effect of unprocessed capsid on the production and infectivity of dengue virus 2 (DENV2) pseudoviral particles. The results showed that (1) both mature and unprocessed capsids of DENV2 were equally efficient in the viral RNA packaging and also in the assembly of infective particles; (2) DENV2 variants, in which the viral and host mediated cleavage of Ca peptide were independent, produced significantly higher levels of infective particles. Overall, this study demonstrated that unlike other flaviviruses, DENV2 capsid does not require a cleavable Ca sequence, and the sequential cleavage is not an obligatory requirement for the morphogenesis of infective pseudoviral particles.
Highlights
Dengue virus (DENV), a member of genus Flavivirus and family Flaviviridae, is one of the major emerging arthropod-borne pathogens infecting millions of people worldwide
C-capsid anchor (Ca) were used: one that was not cleaved by the WNV protease, where the first amino acid of Ca was Thr(T101), and one carrying the T101G mutation that was cleaved by the WNV protease (termed, respectively, C-CaT and C-CaG (Figure 1a)
The flavivirus Ca plays the role of a signal sequence for PrM translocation into the endoplasmic reticulum (ER) lumen
Summary
Dengue virus (DENV), a member of genus Flavivirus and family Flaviviridae, is one of the major emerging arthropod-borne pathogens infecting millions of people worldwide. DENV is an enveloped virus having a single copy of positive sense RNA genome of approximately 11 kb in length. The viral genome encodes for a single polyprotein, which traverses the endoplasmic reticulum (ER) membrane multiple times and is co- and post-translationally processed into 10 viral proteins by viral and host proteases [2]. The virus-encoded serine protease (NS2B/NS3) and the cellular signal peptidase catalyse cleavages of the polyprotein precursor in the cytosolic side and in the lumen of the ER, respectively. Another protease, putatively located inside the ER, is required for processing at the carboxy terminus of the flavivirus protein NS1 [3,4]. Mature virions contain multiple copies of the C protein encapsulating the RNA genome to form the viral nucleocapsid [5,6,7] which is surrounded by a host cell lipid bilayer derived from the ER, embedded with 180 copies of M and E proteins
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