Manipulation of nonclassical ubiquitin signaling by pathogenic bacteria

Manipulation of the host ubiquitin signaling system is emerging as a common and critical mechanism of virulence among pathogenic bacteria. In some cases, such as the intracellular pathogens Legionella pneumophila and Shigella flexneri, ubiquitin regulation is the focus of a significant proportion of the bacterial repertoire of secreted effectors (10% and 30%, respectively). While many of these bacterial effectors hijack classical aspects of the ubiquitin system, such as proteasomal degradation and immune signaling, others target nonclassical ubiquitin signals that are less well understood. These include so-called atypical polyubiquitin chain types, such as Lys6-linked chains, for which specific regulators and functions within human biology have remained elusive. Recent studies have also identified bacterial manipulation of so-called noncanonical ubiquitination, including modification of non-lysine as well as non-proteinaceous targets. Lastly, in select cases such as L. pneumophila, bacteria can impose an entirely orthogonal form of ubiquitin signaling that looks and behaves nothing like the eukaryotic system. Herein, we will review the most recent discoveries in bacterial manipulation of nonclassical ubiquitin signaling.