Search

APOBEC3A (A3A) is a cytidine deaminase that inactivates a variety of viruses through introduction of lethal mutations to the viral genome. Additionally, A3A can suppress HIV-1 transcription in a deaminase-independent manner by binding to the long terminal repeat of proviral HIV-1. However, it is unknown whether A3A targets additional host genomic loci for repression. In this study, we found that A3A suppresses gene expression by binding TTTC doublets that are in close proximity to each other. However, one TTTC motif is sufficient for A3A binding. Because TTTC doublets are present in interferon (IFN)-stimulated response elements (ISRE), we hypothesized that A3A may impact IFN-stimulated gene (ISG) expression. After scanning the human genome for TTTC doublet occurrences, we discovered that these motifs are enriched in the proximal promoters of genes associated with antiviral responses and type I IFN (IFN-I) signaling. As a proof of principle, we examined whether A3A can impact ISG15 expression. We found that A3A binding to the ISRE inhibits phosphorylated STAT-1 binding and suppresses ISG15 induction in response to IFN-I treatment. Consistent with these data, our RNA-sequencing analyses indicate that A3A loss results in increased IFN-I–dependent induction of several ISGs. This study revealed that A3A plays an unexpected role in ISG regulation and suggests that A3A contributes to a negative feedback loop during IFN signaling.

Iniquez et al. (1) claim that ERVmap (2) contains methodological errors and Telescope is more accurate in assigning ambiguous reads (1, 3). Telescope detected 19 elevated and 4 repressed endogenous retroviruses (ERVs), while ERVmap found 124 elevated ERVs (2). Iniquez et al. (1) claim that this difference is due to methodological flaws in our read alignment, ERV annotation, and failure to account for sequencing platform variance. We disagree with all 3 points for the following reasons. ERVmap identifies a best read match through stringent filtering criteria put forth by experts (4, 5). In the absence of a gold standard to call multimapped reads, we intentionally over-discard to avoid miscalling. ERVmap identifies one best … [↵][1]1To whom correspondence may be addressed. Email: akiko.iwasaki{at}yale.edu. [1]: #xref-corresp-1-1