Functions of Delta Antigen Acetylation

HDAg is an acetylated protein and mutation at lysine 72 of S-HDAg affects its subcellular localization as well as viral RNA replication. How does acetylation of S-HDAg modulate the HDV life cycle?

Acetylation has been demonstrated to occur on a wide spectrum of cellular proteins as well as viral proteins and affect these factors' functions and activities (for reviews see Chan and La Thangue 2001; Goodman and Smolik 2000; Greene and Chen 2004; Yang 2004; and references therein). The K72R mutant of S-HDAg displayed a different subcellular distribution pattern from that of the wild-type. Considering the cases that acetylation is crucial for nuclear accumulation of HNF4 (hepatocyte nuclear factor-4) (Soutoglou et al. 2000), MHCII (major histocompatibility class II) trans-activator CIITA (Spilianakis et al. 2000), NF-kB (Chen et al. 2001), and Signal transducers and activators of transcription 3 (Stat 3) (Wang et al. 2005), acetylation on K72 of HDAg is likely to be the signal to modulate its nuclear localization. Moreover, S-HDAg could stimulate the transcription elongation of pol II (Yamaguchi et al. 2001), which is believed to be responsible for the replication of HDV genomic RNA from antigenomic RNA (Macnaughton et al. 2002; Moraleda and Taylor 2001). It may explain the mechanism that non-nucleoplasmic localization of K72R mutant impairs the accumulation of genomic RNA when antigenomic RNA was introduced to cells as template for replication. Although amino acids 68-88 of HDAg had been identified as a bipartite nuclear localization signal (NLS) (Chang et al. 1992; Xia et al. 1992), it is unlikely that K72R mutant of S-HDAg impairs the NLS since treatment with leptomycin B, an inhibitor for CRM-1 dependent nuclear export pathway, could retain K72R mutant of S-HDAg in the nucleus (Mu et al. 2004). S-HDAg has been demonstrated to interact with nuclear proteins such as RNA polymerase II (Yamaguchi et al. 2001), B23 (Huang et al. 2001), nucleolin (Lee et al. 1998) and SC35 (Bichko and Taylor 1996). Since lysine acetylation has also been reported to affect protein-protein interactions (Kiernan et al. 1999; Zhang et al. 2001), the poor nuclear retention ability of the K72R mutant may suggest that acetylation is required for the interaction of S-HDAg with these proteins.

Furthermore, acetylation of K72 may also be able to modulate the interaction of S-HDAg and HDV RNA, just like the cases that acetylation of lysine residues present on the tails of core histones by CBP/p300 weakens internucle-

osomal interactions (Bannister and Kouzarides 1996; Ogryzko et al. 1996) and acetylation of HIV Tat promotes its dissociation from TAR (Tat transactivation response region) RNA (Kiernan et al. 1999).

Acetylation of lysine residues of several proteins, such as histones, p53, HIV Tat, and MyoD, can form specific sites to interact with bromodomain of HATs such as Gcn5, PCAF, and CBP so as to exert specific activities (for reviews see Yang 2004; and references therein). In contrast, acetylation of the lysine residue(s) adjacent to the binding motif of some proteins, such as activator of retinoid receptor (ACTR) (Chen et al. 1999b) and adenovirus E1A (Zhang et al. 2000), can hinder the access of its binding partners. The acetylation of S-HDAg may thus either recruit a transcriptional coactivator or block a negative regulator to facilitate HDV replication.

Protein lysine acetylation can modulate several functions of cellular and viral proteins. Further studies are required to verify the function(s) of acety-lation on S-HDAg and HDV life cycle.

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