BCA2 (Breast Cancer-Associated gene 2, also known as RNF115, ZNF364 or Rabring7) is a cytoplasmic RING-finger E3 ubiquitin ligase that is upregulated in most breast cancer cell lines in response to estrogen. A recent study showed that BCA2 interacts with the cytoplasmic domain of tetherin/BST2 to promote the internalization and 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 not expressing tetherin.
However, here we show for the first time that BCA2 also inhibits virus production in a tetherin-independent manner by reducing the cellular levels of HIV-1 Gag, and that this activity requires the E3 ligase activity. 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 impedes virus assembly and release. We want to formally address this hypothesis by characterizing the molecular mechanism(s) of the tetherin-dependent and tetherin-independent antiviral activity of BCA2 (Specific Aim 1) and by identifying the molecules and cellular pathways that participate in the regulation of BCA2’s activity (Specific Aim 2). A better understanding of the innate mechanisms that limit virus production will help in the elaboration of antiretroviral drugs to 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.
Field of science
- /medical and health sciences/clinical medicine/oncology/cancer
- /natural sciences/physical sciences/theoretical physics/particles
- /medical and health sciences/clinical medicine/oncology/cancer/breast cancer
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