Abstract
The hepatitis B virus (HBV) Core protein encodes a late (L)-domain like motif (129PPAYRPPNAP138) that has been purported to serve as a docking site for recruitment of host factors such as Nedd4 that can mediate viral particle release from infected cells. However, mutation of this region of Core typically disrupts nucleocapsid formation in the cytoplasm, making it difficult to ascertain if the Core PPAY motif constitutes a functional L-domain that mediates HBV release in the context of replicating virus. Since many viral L-domains are functionally interchangeable between different virus families, and such swapping experiments have been used as a tool to identify other viral sequences with L-domain activity, we generated chimeric constructs between murine leukemia virus (MLV) Gag and HBV Core to determine if the potential HBV L-domain motif is sufficient to stimulate virus release. We found that the HBV Core PPAY motif, but not the PNAP motif, demonstrates L-domain activity in the context of MLV replication to direct virus release and infectious virion production. Additionally, we found that overexpression of the cellular Nedd4 or WWP1 ubiquitin ligases stimulates release of a partially defective PPAY domain mutant, providing further evidence supporting a role for the Nedd4 ubiquitin ligase in promoting HBV release. These studies lend further insight into the mechanisms used by HBV to mediate its release from infected cells.
Highlights
Current therapies for chronic hepatitis B virus (HBV) infection include antiviral drugs that block HBV genome replication, such as adefovir and entecavir, or interferon-a (IFN-a), which stimulates the immune response for clearance of the virus [1,2]
The YxxL motif found in the structural proteins of EIAV [22,23,24], Sendai virus [25], and HIV-1 [23,24,26], is responsible for binding Alix (ALG-2interacting protein X), an adapter protein that recruits the viral protein to the multivesicular body (MVB) by interacting with both Tsg101 of ESCRT-I and CHMP4 of ESCRT-III [23,27]
Functional replacement of the endogenous Gag PPPY motif by the Core sequence can be attributed to the PPAY motif since that sequence alone can induce murine leukemia virus (MLV) release at levels comparable to wild-type Gag while the PNAP sequence alone lowers MLV release to levels similar to that observed for the 4A mutation (Fig. 2A and B)
Summary
Current therapies for chronic hepatitis B virus (HBV) infection include antiviral drugs that block HBV genome replication, such as adefovir and entecavir, or interferon-a (IFN-a), which stimulates the immune response for clearance of the virus [1,2]. These treatments are limited by harmful side effects, inadequate availability in developing countries, costliness, and viral resistance. To ensure access to the endocytic machinery, several viruses including HTLV-1 [13,16], Ebola [28], HIV [29] and MLV [30] contain more than one type of motif within their structural proteins that display complimentary roles in mediating release
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