Phosphorylation of S177, acetylation of K72 and methylation of R13 of S-HDAg could all modulate the replication of HDV genomic RNA from antigenomic RNA but not replication of HDV genomic RNA from antigenomic RNA. These results suggest that PTMs of S-HDAg play critical roles for its functions to facilitate the replication of HDV genomic RNA. The different requirements of S-HDAg for the replication of genomic and antigenomic RNA are also consistent with the previous suggestion that rolling circle replication of hepatitis delta virus RNA is carried out by different cellular RNA polymerase machineries (Macnaughton et al. 2002; see also the chapter by T.B. Macnaughton and M.M.C. Lai, this volume). The crosstalk between these different PTMs of S-HDAg and their roles in the HDV life cycle require further evaluation.

Other PTMs such as sumoylation, ubiquitination, and ADP-ribosylation, occur on several cellular proteins as well as viral proteins and modulate their biological functions. Whether these modifications are present on HDAg have not yet been identified.

In conclusion, the PTMofHDAgmay makethemmoreversatile. Dissecting the exact function of individual isoforms will become an important area of HDV virology. Useful state-of-art tools, such as LC/MS/MS and PTM-specific antibodies, may help to relate the modified HDAg to functions.

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