ORF57/MTA in KSHV Biology and Pathogenesis: Update From 2015

Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, also known as MTA, is a viral nonstructural protein that belongs to a conserved family of functionally related proteins encoded by all herpesviruses. As an RNA-binding protein, ORF57/MTA functions as a key post-transcriptional regulator of viral gene expression and is essential for efficient viral replication and production of infectious virions. ORF57/MTA features two distinguishable domains: an intrinsic disordered N-terminal domain or NTD for protein-protein and protein-RNA interactions and a structural α-helix-rich C-terminal domain or CTD for ORF57/MTA dimerization to prevent its proteasome degradation. ORF57/MTA enhances viral gene expression by promoting RNA stability, RNA splicing, and translation of viral transcripts through its NTD domain in cooperation with host/viral cofactors as distinct individual ribonucleoprotein complexes. To mediate these diverse activities, ORF57/MTA binds MTA-responsive elements (MREs) within target RNAs in a sequence and structural motif-dependent manner. Most recent progresses in this update since 2015 include determination of ORF57/MTA domain structure and the crystal structure of its CTD, discovery of a novel role of ORF57/MTA in counteracting cellular innate immune responses through modulation of RNA granule biogenesis, genome-wide identification of viral and host RNAs as ORF57/MTA targets, and elucidation of long-distance viral RNA splicing crossing a large part of the KSHV genome. Collectively, these findings represent significant steps toward our understanding of ORF57/MTA-mediated regulation of not only viral but also host gene expression, as exemplified by ORF57/MTA regulation of FOS expression. Nevertheless, many aspects of ORF57/MTA function remain to be determined and warrant future investigation.