Abstract
SUMOylation is a highly dynamic ubiquitin-like post-translational modification that is essential for cells to respond to and resolve various genotoxic and proteotoxic stresses. Virus infections also constitute a considerable stress scenario for cells, and recent research has started to uncover the diverse roles of SUMOylation in regulating virus replication, not least by impacting antiviral defenses. Here, we review some of the key findings of this virus-host interplay, and discuss the increasingly important contribution that large-scale, unbiased, proteomic methodologies are making to discoveries in this field. We highlight the latest proteomic technologies that have been specifically developed to understand SUMOylation dynamics in response to cellular stresses, and comment on how these techniques might be best applied to dissect the biology of SUMOylation during innate immunity. Furthermore, we showcase a selection of studies that have already used SUMO proteomics to reveal novel aspects of host innate defense against viruses, such as functional cross-talk between SUMO proteins and other ubiquitin-like modifiers, viral antagonism of SUMO-modified antiviral restriction factors, and an infection-triggered SUMO-switch that releases endogenous retroelement RNAs to stimulate antiviral interferon responses. Future research in this area has the potential to provide new and diverse mechanistic insights into host immune defenses.
Highlights
small ubiquitin-like modifier (SUMO) proteins and other ubiquitin-like modifiers, viral antagonism of SUMO-modified antiviral restriction factors, and an infection-triggered SUMO-switch that releases endogenous retroelement
As discussed above, most studies to date have mainly relied on targeted analysis of specific known proteins of interest that had already been implicated in certain pathways, and their SUMOylation status was investigated by standard techniques such as overexpression, immunoprecipitation, and western blotting
K0 method has proven to be one of the most efficient strategies allowing for routine identification of more than 1000 SUMO2 sites under standard conditions [38]. Given that this system is limited to mono-SUMO2 modification, the approach developed by Galisson et al and Lamoliatte et al, which features all the strengths of ubiquitin remnant profiling, might become increasingly popular
Summary
Since their discovery in 1996 [1], the small ubiquitin-like modifier (SUMO) proteins have emerged as key post-translational modifiers associated with crucial regulatory roles in the cell. SUMO proteins are expressed as precursors that require a proteolytic maturation step before SUMOylation can occur: sentrin-specific proteases (SENPs) cleave the SUMO precursor’s C-terminal tail to expose the diglycine motif essential for subsequent conjugation [8,9]. The target lysine is typically located in a specific consensus motif ψKxD/E (where ψ is a hydrophobic residue, x is any amino acid), that has been identified in more than half of all known SUMO target proteins [11] This process is usually facilitated by SUMO E3 ligases that catalyze the transfer of SUMO from UBC9 onto the target, E3-independent. SUMO specific proteases (e.g., SENP family members) can deconjugate SUMO from its targets (known as deSUMOylation) and are essential for the proteolytic maturation of SUMO precursors by cleaving off C-terminal residues to expose the di-glycine motif that is necessary for conjugation. SUMOylation is a highly dynamic mechanism by which the cell can quickly regulate numerous functional pathways, most notably under various stress conditions, without altering protein synthesis [17]
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