Since posttranslational modification (PTM) by the small ubiquitin-related modifiers (SUMOs) was discovered over a decade ago, a huge number of cellular proteins have been found to be reversibly modified, resulting in alteration of differential cellular pathways. Although the molecular consequences of SUMO attachment are difficult to predict, the underlying principle of SUMOylation is altering inter-and/or intramolecular interactions of the modified substrate, changing localization, stability, and/or activity. Unsurprisingly, many different pathogens have evolved to exploit the cellular SUMO modification system due to its functional flexibility and far-reaching functional downstream consequences. Although the extensive knowledge gained so far is impressive, a definitive conclusion about the role of SUMO modification during virus infection in general remains elusive and is still restricted to a few, yet promising concepts. Based on the available data, this review aims, first, to provide a detailed overview of the current state of knowledge and, second, to evaluate the currently known common principles/molecular mechanisms of how human pathogenic microbes, especially viruses and their regulatory proteins, exploit the host cell SUMO modification system.
Small ubiquitin-related modifier (SUMO) was initially identified as reversible, proteinogenic posttranslational modification (PTM) by different laboratories in the mid-1990s (13,116,122,125,135). Today, it is classified as a member of the ubiquitin-like proteins (Ubls) due to its structural and sequence similarities to ubiquitin (89, 169); however, the surface properties of SUMO are quite distinct. Interestingly, it appears that the characteristic determinants of PTM by Ubls are phylogenetically ancient and may have evolved from biosynthetic pathways via repeated rounds of gene duplication and diversification (75). Consequently, SUMO is expressed by all eukaryotes but is absent from prokaryotes/archaea. Lower eukaryotes have a single SUMO gene, whereas plants and vertebrates express several SUMO paralogues.In vertebrates, two subfamilies, namely, SUMO-1 and SUMO-2/3 proteins, are known. SUMO-2 and SUMO-3 are commonly referred to as SUMO-2/3 due to 98% sequence similarity and the lack, to date, of clearly distinguishable functional differences. Although members of each subfamily are highly similar, SUMO-1 and SUMO-2/3 share only about 50% amino acid sequence identity, although all are ϳ100-residue proteins containing significant primary sequence homology to ubiquitin in the C terminus (ϳ20%) and a short unstructured N-terminal stretch (11,128).Recent research has shown important differences in the molecular functionalities of mammalian SUMO-1 and SUMO-2/3 proteins. The latter is present in higher levels than SUMO-1, whereas the unconjugated pool of SUMO-1 is lower than that of SUMO-2/3. Intriguingly, SUMO-2 and SUMO-3 can be conjugated to target proteins in a chain-wise fashion due to internal SUMO conjugation motifs (SCMs), whereas SUMO-1 lacks this ability. Moreover...
