Apobec-1 Complementation Factor Modulates Liver Regeneration by Post-transcriptional Regulation of Interleukin-6 mRNA Stability

Abstract

Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf ؊/؊ blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf ؉/؊ mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH). To pursue the mechanism of impaired liver regeneration we examined activation of interleukin-6 (IL-6) a key cytokine required for induction of hepatocyte proliferation following PH. Peak induction of hepatic IL-6 mRNA abundance post PH was attenuated >80% in heterozygous Acf ؉/؊ mice, along with decreased serum IL-6 levels. IL-6 secretion from isolated Kupffer cells (KC) was 2-fold greater in wild-type compared with heterozygous Acf ؉/؊ mice. Recombinant ACF bound an AU-rich region in the IL-6 3-untranslated region with high affinity and IL-6 mRNA half-life was significantly shorter in KC isolated from Acf ؉/؊ mice compared with wild-type controls.These findings suggest that ACF regulates liver regeneration following PH at least in part by controlling the stability of IL-6 mRNA. The results further suggest a new RNA target and an unanticipated physiological function for ACF beyond apoB RNA editing.Protein-RNA interactions play an important role in posttranscriptional regulation of gene expression, including nuclear mRNA splicing, polyadenylation, and editing as well as cytoplasmic RNA transport, stability, and translation. The protein components required for these various modifications and the pathways involved in their physiological regulation has attracted considerable interest in view of the importance of post-transcriptional modifications in amplifying the genetic repertoire of the host organism (1). Of the two major classes of post-transcriptional RNA editing, C to U RNA editing of mammalian apolipoprotein B (apoB) mRNA has been extensively studied and the minimal core protein components defined (2).ApoB RNA editing is mediated by a multicomponent protein complex with a minimal core containing Apobec-1, the catalytic cytidine deaminase (3) and Apobec-1 complementation factor (ACF), 2 the RNA binding subunit (4, 5). ACF contains three copies of an RNA recognition motif (RRM) identified in other proteins as functioning in protein-RNA interactions and whose modular design and multiplicity likely contribute to refining the specificity and affinity of binding to target RNAs (1). ACF anchors Apobec-1 in an optimal configuration relative to the targeted cytidine within the nuclear apoB RNA and binds with high affinity to an AU-rich region 3Ј of the edited base (4, 6).Although much has been learned about the functional domains in ACF that mediate apoB RNA binding there remain unanswered questions concerning the range of target RNAs and cell-specific factors that influence ACF-RNA binding and its physiological consequences. ...

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

“…S3). Staining in the liver was strong in both cytoplasm and nucleus at P0 and P21 but was largely circumscribed within nucleus of hepatocytes in adults, in accordance with previous studies (76,78). Similarly, weak expression of A1CF in muscle (76) was confirmed at all time points in our study (Fig.…”

Role of the Gut in Lipid Homeostasis

“…Other work has examined the parallel possibility that alternate (non-apoB RNA) targets exist for ACF, particularly in view of the observation that germline deletion of ACF is early embryonic lethal (18). These findings were extended recently with the finding that ACF modulates cytokine (specifically interleukin 6) mRNA stability (20). Taken together, the findings suggest that apobec-1 and ACF each have a range of targets distinct from apoB mRNA, whose biological implications have yet to be formally defined.…”

APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo

“…This report does not represent the first suggestion that A1CF may be important in nonediting-related RNA biology. In hepatic cells, A1CF has been shown to regulate both the stability (Blanc et al 2010) and the subcellular localization of specific mRNAs (Galloway et al 2010). Additional work demonstrated that A1CF behaves as a nuclear shuttling protein (Blanc et al 2003), and the shuttling is mediated by its interaction with APOBEC1 (Chester et al 2003).…”