NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

Taking the positive view that Ap 4 A is a bona fide regulator, what conclusions can be drawn about its principal intracellular role(s)? Rapid suppression of interferon responses after activation of the initial signal transduction pathways is an essential part of the overall immune response to pathogens to avoid the potential toxicity of the many anti-viral, pro-apoptotic, and anti-proliferative proteins that are induced. Therefore, the NuKO phenotype may reflect the activation of these feedback mechanisms. Alternatively, components from infecting pathogens such as proteins or 5 0 -ppp RNAs may actively cause the increased intracellular Ap 4 A by inhibiting NUDT2 in order to down-regulate the immune responses. Poliovirus infection is known to cause a slight (2-fold) increase in Ap 4 A [162] while the SARS coronavirus protein 7a physically interacts with NUDT2, although the effect of this on the level of Ap 4 A is not known [163] . Recently, it has been shown that the viral-induced mediator of the interferon response, cyclic GAMP, can be transferred from cell to cell inside newly-formed virions, and it has been speculated that this is a protective, host-regulated mechanism to rapidly establish an antiviral state in newly infected cells [164, 165] . It is equally interesting to speculate that viruses may also package Ap 4 A into new virions to counteract this. With regard to bacterial pathogens, the two types of bacterial Ap 4 A hydrolase, the asymmetrically-cleaving NUDT2 homologue RppH (also known as YgdP or IalA) and the unrelated symmetrically-cleaving ApaH, have been classified as invasion proteins and are required for optimal survival of bacteria during cellular invasion [166] [167] [168] [169] . They may help to prevent high host cell Ap 4 A induced by infection-associated stress from inhibiting essential bacterial functions.