Abstract
BackgroundProteins associated with the late endosome (LE) appear to play a central role in the envelopment of a number of taxonomically diverse viruses. How viral proteins interact with LE-associated proteins to facilitate envelopment is not well understood. LE-derived transport vesicles form through the interaction of Rab9 GTPase with cargo proteins, and TIP47, a Rab9-specific effector protein. Vaccinia virus (VV) induces a wrapping complex derived from intracellular host membranes to envelope intracellular mature virus particles producing egress-competent forms of virus.ResultsWe show that VV p37 protein associates with TIP47-, Rab9-, and CI-MPR-containing membranes. Mutation of a di-aromatic motif in p37 blocks association with TIP47 and inhibits plaque formation. ST-246, a specific inhibitor of p37 function, inhibits these interactions and also blocks wrapped virus particle formation. Vaccinia virus expressing p37 variants with reduced ST-246 susceptibility associates with Rab9 and co-localizes with CI-MPR in the presence and absence of compound.ConclusionThese results suggest that p37 localizes to the LE and interacts with proteins associated with LE-derived transport vesicle biogenesis to facilitate assembly of extracellular forms of virus.
Highlights
Proteins associated with the late endosome (LE) appear to play a central role in the envelopment of a number of taxonomically diverse viruses
To determine if the block in enveloped virus (EEV) production was due to a lack of intracellular enveloped virus (IEV) production, Vaccinia virus (VV) was propagated in the presence and absence of ST-246, and virions were radiolabeled with tritiated thymidine and fractionated by equilibrium centrifugation (Fig. 1A)
In the presence of ST-246, only a single peak of radioactivity was observed from the cell associated virus fractions that migrated at the same density as IMV particles and no peak of radioactivity could be detected in virus from the culture medium
Summary
Proteins associated with the late endosome (LE) appear to play a central role in the envelopment of a number of taxonomically diverse viruses. Vaccinia virus (VV) induces a wrapping complex derived from intracellular host membranes to envelope intracellular mature virus particles producing egress-competent forms of virus. Golgi localization and intracellular trafficking of p37 requires palmitylation of two cysteine residues at positions 185 and 186 [8] as well as a putative phospholipase motif composed of histidine, lysine, aspartic acid (HKD) [5]. Targeted mutagenesis of these cysteine residues or amino acids within the HKD motif alters the intracellular distribution of p37 and inhibits IMV wrapping [9,10,11,12]
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