A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems

Zhang, Dapeng; Iyer, Lakshminarayan M.; Aravind, L.

The extensive spread of the US22 group of the SUKH superfamily across unrelated or distantly related DNA viruses of animals suggests that it confers an important advantage to these viruses. This is also supported by the lineage-specific expansion in betaherpesviruses of the SUKH superfamily in the form of multigene arrays similar to what is seen in bacteria ( Figure 2 ). Indeed multiple studies suggest that distinct copies of the proteins in herpesviruses are required for effective survival and replication of the virus in their hosts. For instance, mutagenesis of two SUKH superfamily paralogs M142 and M143 in the murine cytomegalovirus was shown to be essential for survival of the virus itself, whereas mutagenesis of other paralogs M139, M140 and M141 specifically prevents its replication in macrophages (77) . Other studies indicated that M142 and M143 form a heterotetrameric complex which counters the action of the host protein kinase R (PKR) in shutting down viral protein synthesis (78) (79) (80) (81) . The human cytomegalovirus SUKH superfamily proteins TRS1 and IRS1 have been shown to similarly counter the PKR and the dsRNA dependent arm of the anti-viral response (78, (82) (83) (84) (85) (86) . Another paralog UL38 inhibits the host cell stress responses by antagonizing the tuberous sclerosis protein complex in the endoplasmic reticulum (87, 88) and counters apoptosis in conjunction with yet another paralog UL36 (89, 90) . In light of these observations it appears that the viral versions of the SUKH superfamily are deployed to counter different facets of the host anti-viral and stress response. By analogy to the bacterial versions, which function as immunity proteins, we propose that the viral SUKH domain proteins in general bind diverse host proteins that are used against the virus. Here again the special ability of the SUKH scaffold to bind diverse proteins appears to have been exploited by the virus as a flexible binding interface to neutralize a diverse group of host anti-viral defenses.