Disease relevance of APOBEC3G

• The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif [1].
• Because DNA deamination takes place after virus entry into target cells, APOBEC3G function is dependent on its association with the viral nucleoprotein complexes that synthesize cDNA and must therefore be incorporated into virions as they assemble in infected cells [1].
• The APOBEC3G enzyme inhibits the replication of retroviruses by deaminating nascent retroviral cDNA cytosines to uracils, lesions that can result in lethal levels of hypermutation [2].
• Two members of this family, APOBEC3G and APOBEC3F, have been found to have potent activity against virion infectivity factor deficient (Deltavif) human immunodeficiency virus 1 (HIV-1) [3].
• The reduction in APOBEC3G incorporation was equivalent to the reduction in the total RNA present in the nucleocapsid mutant virions [4].

Psychiatry related information on APOBEC3G

• Our findings provided the first evidence showing that APOBEC3G is induced by IFN stimulation in human hepatocytes and thus could be involved in host defense mechanisms directed against hepatitis viruses [5].
• CONCLUSIONS: Apart from patients in the preclinical phase of Alzheimer's disease, the ARCD category includes non-demented patients who have brain dysfunction that may represent a distinct clinical entity [6].
• METHODS: Double-sandwich ELISA (Innotest htau antigen and beta-Amyloid (1-42), Innogenetics) were used to quantify the above markers in a total of 20 patients with ARCD, 33 AD patients with mild to moderate dementia and 50 mentally intact subjects [7].
• METHODS: All persons aged 60 years or older who were residents of the rural area of Wadi Ara were examined for identification of DAT, vascular dementia (VaD) and conversion from age related cognitive decline (ARCD) to DAT using DSM-IV criteria and a semi-structured questionnaire for collection of demographic and medical data [8].

High impact information on APOBEC3G

• It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells [9].
• The human protein apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G), also known as CEM-15, mediates a newly described form of innate resistance to retroviral infection by catalyzing the deamination of deoxycytidine to deoxyuridine in viral cDNA replication intermediates [1].
• Using an APOBEC3G-specific antiserum, we now show that Vif prevents virion incorporation of endogenous APOBEC3G by effectively depleting the intracellular levels of this enzyme in HIV-1-infected T cells [10].
• The recently discovered mammalian enzymes, APOBEC3G and 3F, induce guanine-to-adenine hypermutation in retroviruses [11].
• Surprisingly, APOBEC3F and APOBEC3G are extensively coexpressed in nonpermissive human cells, including primary lymphocytes and the cell line CEM, where they form heterodimers [12].

Chemical compound and disease context of APOBEC3G

• To elucidate the mechanism of viral suppression by APOBEC3G, we developed a sensitive cytidine deamination assay and analyzed APOBEC3G virion incorporation in a series of HIV-1 deletion mutants [4].
• Human APOBEC3F and APOBEC3G are specifically incorporated into human immunodeficiency virus type 1 (HIV-1) progeny virions in the absence of virion infectivity factor (Vif), where they deaminate deoxycytidine to deoxyuridine on the minus strand of nascent reverse transcripts [13].
• Recently, the human apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G), first identified as CEM15, was shown to be packaged into retroviral virions and to deaminate deoxycytidine to deoxyuridine in newly synthesized viral minus-strand DNA, thereby inducing G-to-A hypermutation [14].
• Human APOBEC3F and APOBEC3G are double-domained deaminases that can catalyze dC-->dU deamination in HIV-1 and MLV retroviral DNA replication intermediates, targeting T-C or C-C dinucleotides, respectively [15].

Biological context of APOBEC3G

• Our results show that in bacteria this single amino acid substitution controls Vif-dependent blocking of APOBEC3G that is dependent on a strong protein interaction [16].
• Population level analysis of human immunodeficiency virus type 1 hypermutation and its relationship with APOBEC3G and vif genetic variation [17].
• In the absence of Vif, APOBEC3G is encapsidated and blocks virus replication by deaminating cytosines of the viral cDNA [18].
• Complementary function of the two catalytic domains of APOBEC3G [18].
• Here, we demonstrate that it does, as APOBEC3G exerts its antiviral effect during reverse transcription to trigger G-to-A hypermutation in the nascent retroviral DNA [19].

Anatomical context of APOBEC3G

• Anti-viral protein APOBEC3G is induced by interferon-alpha stimulation in human hepatocytes [5].
• Viral replication in various target cells (PBMC and H9, A3.01, U38, and Jurkat cells) and infectivity in single cycle assays in the presence of APOBEC3G were also analyzed [20].
• Unfortunately, APOBEC3B also differs from APOBEC3F and APOBEC3G in that it is not normally expressed in the lymphoid cells that serve as targets for HIV-1 infection [21].
• Distinct Patterns of Cytokine Regulation of APOBEC3G Expression and Activity in Primary Lymphocytes, Macrophages, and Dendritic Cells [22].
• The Anti-HIV-1 Editing Enzyme APOBEC3G Binds HIV-1 RNA and Messenger RNAs That Shuttle between Polysomes and Stress Granules [23].

Associations of APOBEC3G with chemical compounds

• APOBEC3G expression caused a 20-fold increase in frequency of mutation to canavanine-resistance, which was further elevated in a uracil DNA glycosylase-deficient background [2].
• The human apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, or hA3G) protein, provides cells with an intracellular antiretroviral activity that is associated with the hypermutation of viral DNA through cytidine deamination [24].
• Using APOBEC3G deletion and point mutants, we mapped the encapsidation determinant to the Zn(2+) coordination residues of the N-terminal catalytic domain (CD1) [18].
• The levels of APOBEC3G mRNA and protein were unaffected by treatment of proliferating H9 cells with interferons or tumor necrosis factor-alpha but were enhanced up to 20-fold by phorbol myristate acetate [25].
• The antiretroviral activity of the cellular enzyme APOBEC3G has been attributed to the excessive deamination of cytidine (C) to uridine (U) in minus strand reverse transcripts, a process resulting in guanosine (G) to adenosine (A) hypermutation of plus strand DNAs [26].

Physical interactions of APOBEC3G

• Further, the N-terminal half determined RNase sensitivity and was necessary for the high molecular mass complex assembly of APOBEC3G but not APOBEC3F [27].

Regulatory relationships of APOBEC3G

• CONCLUSION: APOBEC3G is incorporated into HTLV-1 virions and inhibits the infection of HTLV-1 without exerting its cytidine deaminase activity [28].
• Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G [29].
• Mutations of conserved hydrophobic residues (Ile-120, Ala-123, and Leu-124) located between the two Cys residues in the HCCH motif disrupt binding of the zinc-coordinating region to Cul5 and inhibit APOBEC3G degradation [30].

Other interactions of APOBEC3G

• Although APOBEC3G and -3H did not influence L1 retrotransposition notably, expression of APOBEC3B, -3C, and -3F inhibited transposition by approximately 75% [31].
• APOBEC3G is closely related to APOBEC1, the central component of an RNA-editing complex that deaminates a cytosine residue in apoB messenger RNA [19].
• These findings suggest that the E3 ubiquitin ligase activity of the Vif-BC-Cul5 complex is essential for Vif function against APOBEC3G [32].
• IFN regulatory factor elements that are important for IFN-inducible promoter activity were identified 5' upstream from the human APOBEC3G gene [5].
• Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is a host cytidine deaminase that is packaged into virions and confers resistance to retroviral infection [4].

Analytical, diagnostic and therapeutic context of APOBEC3G

• APOBEC3G deaminates deoxycytidines in minus strand DNA to deoxyuridines, resulting in G to A hypermutation and viral inactivation [4].
• The HIV-1 Vif-resistant mutant APOBEC3G could provide a gene therapy approach to combat HIV-1 infection [14].
• Because APOBEC3G contains two such motifs, we used site-directed mutagenesis of conserved residues to assess each region's contribution to anti-HIV-1 activity [26].
• We show that human APOBEC3G is a potent inhibitor of FV infectivity in cell culture experiments [33].
• In activated CD4+ T cells, cytoplasmic APOBEC3G resides in an enzymatically inactive, high-molecular-mass (HMM) ribonucleoprotein complex that converts to an enzymatically active low-molecular-mass (LMM) form after treatment with RNase [34].

References