Viruses, SUMO, and immunity: the interplay between viruses and the host SUMOylation system

Abstract

The conjugation of small ubiquitin-like modifier (SUMO) proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for a variety of downstream cellular activities. Several studies describe SUMOylation as an essential post-translational modification for successful viral infection across a broad range of viruses, including RNA and DNA viruses, both enveloped and un-enveloped. These viruses include but are not limited to herpes viruses, human immunodeficiency virus-1, and coronaviruses. In addition to the SUMOylation of viral proteins during infection, evidence shows that viruses manipulate the SUMO pathway for host protein SUMOylation. SUMOylation of host and viral proteins greatly impacts host innate immunity through viral manipulation of the host SUMOylation machinery to promote viral replication and pathogenesis. Other post-translational modifications like phosphorylation can also modulate SUMO function. For example, phosphorylation of COUP-TF interacting protein 2 (CTIP2) leads to its SUMOylation and subsequent proteasomal degradation. The SUMOylation of CTIP2 and subsequent degradation prevents CTIP2-mediated recruitment of a multi-enzymatic complex to the HIV-1 promoter that usually prevents the transcription of integrated viral DNA. Thus, the "SUMO switch" could have implications for CTIP2-mediated transcriptional repression of HIV-1 in latency and viral persistence. In this review, we describe the consequences of SUMO in innate immunity and then focus on the various ways that viral pathogens have evolved to hijack the conserved SUMO machinery. Increased understanding of the many roles of SUMOylation in viral infections can lead to novel insight into the regulation of viral pathogenesis with the potential to uncover new targets for antiviral therapies.

Keywords: Infection; Post-translational modifications; SUMOylation; Virus.

Fig. 1

SUMOylation: the Small Ubiquitin-related Modifier (SUMO) conjugation-deconjugation pathway. SUMO proteins are processed by a SUMO-specific protease to expose a diglycine (-GG) motif, resulting in a mature SUMO peptide (~ 12 kDa). Mature SUMO is activated in an ATP-dependent reaction, creating an intermediate thioester bond between the active site of SUMO and the heterodimeric E1-activating enzyme (Aos1/Uba2). Following activation, SUMO is transferred from the E1 enzyme to Ubc9, the central E2 enzyme. Ubc9 may then directly facilitate the binding of SUMO to the target substrate (not shown), or may recruit an E3 enzyme, which functions in substrate recognition and specificity. SUMO is removed from target proteins (deconjugation) by SUMO proteases, making SUMOylation a reversible process. AMP adenosine monophosphate, PPi pyrophosphate, SAE1/SAE2 SUMO-activating enzyme

Fig. 2

Viral targeting of Ubc9. ADV Gam1 and HPV E6 induce the degradation of Ubc9, promoting viral replication. ADV E1A interaction with Ubc9 blocks SUMOylation of other cellular substrates and restricts innate immune responses. Conversely, EBV LMP1, HCMV UL44, Hantavirus NP, HPV E2, and HIV gp120 increase the SUMOylation of cellular substrates, modulating viral replication. ADV adenovirus, Gam1; HPV human papilloma virus; EBV Epstein-Barr virus; LMP1 latent membrane protein 1; HCMV human cytomegalovirus; NP nucleocapsid protein

Fig. 3

Viral targeting of SUMO E3 ligases. The HSV ICP0 protein disrupts the activity of PIAS family members and counteracts innate immune responses. Parvovirus B19, HSV, and HCV induce the expression of PIAS1, 3, and/or 4 resulting in regulation of host immune responses and inflammation. The HIV capsid protein interacts with RanBP2 to facilitate nuclear import of HIV DNA. HSV interacts with RanBP2 and disrupts its association with other NPC members, but the overall functional consequence has not been described. HSV herpes simplex virus, ICP0 infected cell polypeptide 0, PIAS protein inhibitor of activated STAT, HCV hepatitis C virus, NS1 nonstructural protein

Fig. 4

Viral targeting of SUMO-specific proteases (SENPs). KHSV LANA and EBV LMP1 block cellular SENP by inhibiting its transcription and facilitating its degradation, respectively. The HBV HBx protein induces SENP activity and facilitates de-SUMOylation of cellular substrates. KHSV Kaposi’s sarcoma-associated herpesvirus, LANA latency-associated nuclear antigen, EBV Epstein-Barr virus, LMP1 latent membrane protein 1, SENP SUMO-specific protease, HBV hepatitis B virus, HBx hepatitis B virus protein X