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shrikant anant et al.

Further studies demonstrated that CUGBP2 is a competitive inhibitor of the RNA-editing reaction, which can be rescued by addition of either increasing amounts of apobec-1 or ACF, but not apoB RNA (68). This suggests that CUGBP2 exerts its effects by disrupting the apobec-1-ACF interaction. Further, protein-protein interaction and enzyme kinetic studies are required to fully deduce the mechanism of CUGBP2 action in the RNA-editing process.

a. CUGBP2: mRNA Splicing, Stability, and Translational Control Functions? In addressing its potential biological functions, it is worth emphasizing that CUGBP2 is ubiquitously expressed at low levels, but at higher levels in skeletal and cardiac muscle, sites where neither apobec-1 or apoB RNA is expressed and no C to U RNA editing occurs (68). An important feature in myotonic dystrophy is muscle wasting and weakness, features that emerge in the setting of expanded CUG repeats within the myotonic dystrophy-related protein kinase, DMPK (122). These expanded CUG repeats were initially postulated to bind to proteins and sequester them in the nucleus, resulting in loss of their normal RNA processing function. Indeed, CUGBP2 was initially identified to bind to the expanded CUG triplet repeats present in the 3'UTR of DMPK (121).

What cellular function of CUGBP2 is disrupted in myotonic dystrophy? CUGBP2 was identified to bind and regulate alternative splicing of the human cardiac troponin T pre-mRNA (123-125). The observation that splicing of cardiac troponin T is also disrupted in striated muscle of myotonic dystrophy patients, implies indirectly that CUGBP2 may exert a role in alternative splicing in this setting (126-128). In this regard, it should be noted that a muscle-specific chloride channel, CIC-1, and insulin receptor pre-mRNAs are aberrantly spliced in striated muscle of myotonic dystrophy patients (126,129,130). The mechanistic relationship of these observations to disease pathogenesis will require further study. Adding to the complexity in this disease, there is increased expression of CUGBP1, a homolog of CUGBP2, in the muscle of myotonic dystrophy patients (126). CUGBP1 is also implicated in the aberrant splicing function (126,131), and its role in the setting of myotonic dystrophy will need further direct evaluation. More recently, CUGBP2 has been demonstrated to modulate mRNA stability and translation functions (132). CUGBP2 was observed to bind AU-rich sequences in the 3'UTR of cyclooxygenase-2 mRNA and stabilize the mRNA, yet paradoxically inhibits its translation (132). Furthermore, CUGBP2 overexpression in a colon cancer cell line, HT-29, resulted in apoptosis, suggesting an important role for this protein in cell turnover and proliferation (132). Taken together, these studies suggest that CUGBP2 and its homologs may play a role in various cellular functions, including regulating apoB mRNA editing in epithelial cells as well as possibly in disorders associated with altered RNA splicing and translation.

C. Additional Factors—Regulators of RNA Editing?

Four cellular proteins have been identified either as a apobec-1 RNA-binding protein (ABBP-1, ABBP-2, hnRNP-C) or a member of the editosome complex (AUX240).

ABBP-1 is an alternatively spliced variant of hnRNP-A/B, which was originally identified in a two-hybrid screen of a human placenta cDNA library (71). Confirmation of apobec-1 interaction was performed by immunopreci-pitation assays using in vitro translated proteins (71). In addition, the apobec-1-binding domain in ABBP-1 was mapped to a glycine-rich region, located in the C-terminus of the protein (71). ABBP-1 was also observed to bind apoB RNA in vitro by electrophoretic mobility shift assays (71). Immunodepletion of ABBP-1 in extracts from apobec-1-transfected HepG2 cells reduced apoB RNA editing in vitro (71). Furthermore, antisense cDNA-mediated knockdown of ABBP-1 in HepG2 cells resulted in loss of endogenous apoB mRNA editing (71). Taken together these data suggest that ABBP-1 or another spliced variant of hnRNP-A/B is required for apoB mRNA editing. These findings are intriguing in light of the information that HepG2 cells express ACF, the required complementation factor for C to U editing. The immediate question is how ABBP1 knockdown abrogates apoB RNA editing since ACF itself should continue to be expressed and has been demonstrated alone to complement apobec-1. Further analysis of these ABBP-1 antisense experiments may reveal whether the inhibition was specific for ABBP-1 downregulation or whether ACF expression was inadvertently altered.

ABBP-2 (also known as HEDJ) also identified in a yeast two-hybrid screen of a human placenta library (70). This protein was originally identified as a member of the hsp40 cochaperone family, which is characterized by the presence of a highly conserved J domain involved in protein synthesis, folding, and secretion (70,133). The J domain is a signature of members of the DNAJ family. These chaperones are also involved in reverse translocation and degradation of misfolded proteins in the lumen of the endoplasmic reticulum (133). The J domain interacts with the endoplasmic reticulum-associated Hsp70 in an ATP-dependent manner and is capable of stimulating its ATPase activity (70,133). It is intriguing that apobec-1 interacts with this protein. Similar to ABBP-1, inhibition of ABBP-2/HEDJ expression by transfection of an antisense ABBP-2 cDNA resulted in downregulation of apoB RNA editing

(70). The mechanism of this response is unclear and additional studies will need to address the effects of ABBP-2 expression on the expression and function of ACF.

3. HNRNP-C1

hnRNP-C1 was identified in a yeast two-hybrid screen of a rat liver cDNA library using apobec-1 as bait (67). hnRNP-C1 is an AU-rich RNA-binding protein that binds to nascent transcripts and is involved in spliceosomal assembly and mRNA splicing (134,135). Recombinant hnRNP-C1 bound to the sense strand of apoB RNA, but not the antisense strand (67). Given that apoB RNA is ~ 70% AU-rich in content in the region flanking the edited cytidine, this RNA-binding activity profile suggests that hnRNP-C1 interacts with a specific AU-rich sequence in apoB RNA (67). Further studies narrowed the RNA-binding domain to the N-terminal 104 amino acids in hnRNP-C1, which contains a single RRM (67). Recombinant hnRNP-C1 was observed to inhibit C to U RNA editing, catalyzed by a partially purified fraction from rat liver extracts (67). The mechanism of this competitive inhibition was not due to binding of hnRNP-C1 to apoB RNA, since a deletion mutant of hnRNP-C1 that retained RNA-binding activity, but lacked the leucine-rich repeats, failed to inhibit the RNA-editing reaction (67). Rather, the findings suggest that hnRNP-C1 competitively inhibits apoB RNA editing through protein-protein interactions with apobec-1 and/or other factors in the holoenzyme.

4. AUX240

AUX240 was identified in rat liver extracts using monoclonal antibodies generated against the 27S editosome that was assembled in vitro on a synthetic apoB RNA (72). Immunodepletion of AUX240 from rat liver extracts resulted in significant inhibition of C to U RNA-editing activity (72). Furthermore, addition of the bead-eluted material to rat liver extracts enhanced RNA-editing efficiency (72). However, addition of the immunoadsorbed material alone to the editing reaction in the absence of the additional proteins did not demonstrate any RNA-editing activity (72). These data suggest that the immunoadsorbed material does not contain all the factors necessary to support C to U RNA editing. Taken together, these data offer no clear proof of the involvement of AUX240 in C to U RNA-editing activity. It should be noted that multiple proteins from rat liver extracts coeluted with AUX240 from rat liver extracts, including a protein of 66 kDa which may conceivably be ACF (72). The nature of these other coeluting proteins is currently unknown, but further study will likely be revealing.

V. Summary

C to U editing of a single cytidine at nt 6666 in apoB RNA is mediated by a multicomponent-editing complex, and is regulated by developmental, nutritional, and hormonal factors. Apobec-1 and ACF are components of the minimal-editing enzyme, although other proteins, such as GRY-RBP and CUGBP2, represent likely auxiliary factors of the editing holoenzyme that regulate its activity. Much work remains in this area, including identification of all the factors that comprise the holoenzyme and a characterization of their role in C to U RNA editing. In addition, as implied throughout this report, the proteins that have been currently identified may exhibit other functions in RNA metabolism. It would be interesting to determine whether these other functions, such as pre-mRNA splicing, mRNA stability, and mRNA translation, are related to their intrinsic RNA-editing function. Future studies will likely provide an opportunity to consider these issues in the context of the evolutionary significance of RNA editing and the RNA world.

Acknowledgments

Work cited from the authors' laboratories is supported by the National Institutes of Health grants DK-56260 and HL-38180 to NOD, DK-62265 to S.A., and the Digestive Disease Research Core Center Grant DK-52574. S.A. is a Research Scholar of the American Gastroenterology Association. The authors acknowledge valuable discussions with current and former laboratory members, particularly Jeff Henderson, Susan Kennedy, Debnath Mukhophadyay, and Libby Newberry.

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