BCA2 (Breast Cancer-Associated gene 2, also known as RNF115, ZNF364 or Rabring7) is a RING-finger E3 ubiquitin ligase that is up-regulated in most breast cancer cell lines in response to estrogen. A recent study showed that BCA2 interacts with the cytoplasmic domain of tetherin to promote the internalization and lysosomal degradation of tethered HIV-1 particles, and that the E3 ligase activity of BCA2 is dispensable to enhance the tetherin-mediated restriction of HIV-1. Therefore, BCA2 would act as a tetherin co-factor, lacking antiviral activity in cells that do not express tetherin. However, here we show, fo the first time, that BCA2 inhibits virus production in a tetherin-independent manner by reducing the cellular levels of HIV-1 Gag, and that this activity requires an intact RING-finger domain. Furthermore, we show that BCA2 physically interacts with Gag and promotes its ubiquitination and lysosomal degradation, suggesting that BCA2 may be an innate antiviral factor that interferes with virus assembly. We want to formally address this hypothesis by characterizing the molecular mechanisms of the antiviral activity of BCA2 (Specific Aim 1) and by identifying the molecules that participate in the regulation of BCA2's activity, as well as the cellular pathways that are activated in response to BCA2 (Specific Aim 2). A better understanding of the innate mechanisms that limit virus production will help in the elaboration of antiretroviral drugs o contain virus replication in affected individuals. Therefore, the objectives outlined here are directly relevant to identifying new targets for antiretroviral therapy to control HIV-1 infection.
The studies outlined in this proposal are expected to reveal the molecular mechanism by which BCA2, a RING- finger E3 ubiquitin ligase, inhibits HIV-1 replication. Furthermore, we seek to understand the response elements and cellular pathways that regulate the antiviral activity of BCA2, which will help develop new antiretroviral drugs to contain HIV-1 replication.
|Serra-Moreno, Ruth (2014) The end of Nef's tether. Trends Microbiol 22:662-4|
|Nityanandam, Ramya; Serra-Moreno, Ruth (2014) BCA2/Rabring7 targets HIV-1 Gag for lysosomal degradation in a tetherin-independent manner. PLoS Pathog 10:e1004151|