Effect of prostaglandin A and tunicamycin on rotavirus assembly.

Abstract

To the Editor—Superti et al. [1] describe inhibition of both rotavirus replication and nonstructural protein NSP4 glycosylation as well as decrease in viral protein VP4 and VP7 levels due to prostaglandin A1 (PGA1). Ultrastructural analysis of SA11 rotavirus morphogenesis showed that despite budding of particles into the endoplasmic reticulum (ER), virus maturation was impaired in PGA1-treated cells, with most of the virus particles remaining in “enveloped” particles. Similar morphologic observations have been shown for cells treated with tunicamycin (N-linked glycosylation inhibitor), although tunicamycin inhibits glycosylation of both VP7 and NSP4 [2–5]. Rotaviruses have a unique morphogenesis in which particles obtain a transient membrane envelope that is formed by the budding of subvirus particles into the ER [5]. This transient membrane is lost, and the mature, double-shelled virus particles acquire the two outer capsid proteins (VP4 and VP7) in the ER lumen. The authors considered that in PGA1-treated cells, virus maturation from enveloped particles to double-shelled particles was impaired. However, another interpretation is possible. Recently, we proposed a novel pathway of virus maturation by an exocytosis-like process, probably by a fusion-like mechanism, so that during double-shelled particle assembly, subvirus particles (possibly single-shelled particles) acquire the outer capsid protein during their transport across the ER membrane [6, 7]. The envelope that is formed by the budding process subsequently swells and is ruptured, and single-shelled particles are released later during cytolysis. Thus the budding process may simply serve as a vehicle to transport single-shelled particles from the cytoplasm to the ER lumen. On the basis of our observations and the finding for tunicamycin-treated cells [2–5], it is conceivable that glycosylation of NSP4 is indispensable for double-shelled particle assembly and regulation of transport of single-shelled particles through the ER membrane [6, 7]. Therefore, inhibition of NSP4 glycosylation in PGA1-treated cells, as in the case with tunicamycin, could be responsible for not only the increase in enveloped particles through the budding process, but also the reduction in double-shelled particles through the exocytosis-like process. We agree with the proposal of Superti et al. [1] that PGA1 inhibits rotavirus replication and offers new perspectives in the search for effective therapeutic agents for rotavirus gastroenteritis.