Viral manipulation of cellular protein conjugation pathways: The SUMO lesson

Abstract

Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.

Keywords: Exploitation; Immune evasion; Innate immunity; Small ubiquitin-like modifier; Small ubiquitin-like modifier-ylation; Virus; Virus assembly.

Figure 1

Schematic representation of the small ubiquitin-like modifier conjugation enzymatic cascade. The cartoon schematically represents the enzymatic steps of small ubiquitin-like modifier (SUMO) protein conjugation on lysines of substrate proteins. 1: SUMO protein precursors are processed by SUMO proteases (SENP) that remove the C-terminal tetrapeptide (X) and free the diglycine motif (-GG); 2: The mature form of SUMO is activated by adenylation at the C-terminal diglycine motif by the E1 enzyme (the SUMO activating enzyme, SAE1-SAE2 or AOS1-UBA2) promoting a thioester bond with a conserved Cys of the E1 enzyme; 3: SUMO is then transferred to a Cys on the E2 conjugating enzyme (Ubc9) forming an E2-SUMO thioester; 4: An isopeptide bond is formed between the diglycine motif of SUMO and a lysine (K) residue in the substrate. E3 ligases are dispensable in vitro but most likely required in vivo; 5: SUMO proteins are removed from substrates by the action of SUMO proteases (SENPs) or DeSumoylating-isopeptidase (DeSI) and free SUMO proteins are available for another cycle of conjugation.

Figure 2

Viral proteins exploit small ubiquitin-like modifier at different steps of virus lifecycle. Scheme representing the different stages of viral infection (entry, replication, assembly, release) in host cells. Viral proteins interact with the small ubiquitin-like modifier (SUMO) machinery to promote different steps of viral life cycle, as represented. Viral proteins are designed with their acronym. The asterisk (*) indicates that the marked viral protein has not been formally shown to directly influence viral life cycle by exploiting SUMOylation, but indications of a mechanistic link are known. See text for further details on exploitation of the SUMO machinery by single viral proteins.

Figure 3

Viral proteins exploit small ubiquitin-like modifier to promote immune escape from innate and intrinsic responses. Schematic representation of the strategies used by viral proteins to counteract host innate and intrinsic responses through small ubiquitin-like modifier (SUMO). Viral proteins are designated with their acronym. S stands for SUMO. The asterisk (*) indicates that the marked viral protein has not been formally shown to directly influence cellular antiviral activity by exploiting SUMOylation, but indications of a mechanistic link are known. See text for further details on exploitation of the SUMO machinery by single viral proteins. IFN: Interferon; IRF: IFN regulatory factor; PML-NBs: ProMyelocyticLeukemia nuclear bodies.