Browsing by Subject "Activation-Induced Cytidine Deaminase"

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MMTV encodes a protein antagonist of multiple Apobec family members
(2018-12-04) Bhupindersingh, Gurvani; Dudley, Jaquelin; Tucker, Haley; Sullivan, Christopher; Vasquez, Karen; Ehrlich, Lauren
Mouse Mammary Tumor Virus (MMTV) is a member of the genus Betaretrovirus in the family Retroviridae. MMTV, which primarily induces mammary carcinomas, has been extensively used as a model system to study human breast cancers. Due to its complex organization similar to human retroviruses, such as human immunodeficiency virus type 1(HIV-1) [12], studies of MMTV pathogenesis greatly aid in understanding viral interactions with the natural host immune system. MMTV encodes a 33 kDa regulatory protein, Rem, which is synthesized from a doubly spliced form of viral genomic RNA [23, 48]. The precursor Rem is targeted to the endoplasmic reticulum (ER) for translation and is cleaved by signal peptidase into an N-terminal Signal Peptide (SP) and a C-terminal protein (Rem-CT) [50]. Previous studies have demonstrated that SP (also cleaved from envelope precursor protein) can manipulate the ER-associated degradation pathway (ERAD) and retrotranslocate to the cytoplasm prior to nuclear entry to facilitate export of MMTV RNA [24]. SP thus has an analogous function to HIV-encoded Rev protein. The role of Rem-CT remains unknown. Cytidine deaminases belonging to the apolipoprotein B messenger RNA editing catalytic polypeptide (APOBEC/Apobec) family are restriction factors for human and mouse retroviruses, respectively, as well as for retrotransposons and some DNA viruses [129, 132, 141-150, 162-166]. Murine Apobec3 (mA3)-deficient mice are more susceptible to MMTV infection [179], yet no known MMTV-encoded antagonist of mA3 has been identified. MMTV requires replication through B and T lymphocytes [33, 34, 37], both of which express Apobec family proteins, prior to mammary gland infection and tumorigenesis [93, 97]. Experiments were performed to address the role of Rem C-terminal sequences to antagonize Apobec enzymes and facilitate virus replication in vivo. Previous results have shown that mice infected with Rem-null MMTV developed mammary tumors with a lower incidence and increased latency compared to those infected with wild-type MMTV. Absence of Rem during in vivo infection resulted in lower proviral loads and increased mutations of the viral genome in mammary tumors. These differences were abolished in mice deficient for Activation-Induced Cytidine Deaminase (AID), a primordial member of the Apobec family that plays a role in shaping the adaptive immune response and development of human B-cell lymphomas. Tissue culture experiments revealed that Rem expression targets AID for proteasomal degradation. This study provides evidence that Rem is an HIV-Vif like protein and the first protein inhibitor of AID. In addition, these results suggest that Rem may antagonize other Apobec enzymes