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.

The down-regulation of tryptophan catabolism by Ap 4 A offers a possible explanation as to why, of all the aminoacyl-tRNA synthetases able to generate diadenosine oligophosphates, mammalian tryptophanyl-tRNA synthetase (WRS) is the only one unable to synthesise Ap 4 A. It can only make Ap 3 A [170] . WRS is expressed constitutively in all cells, but can be strongly induced in many non-lymphoid cells, e.g. monocytes, by Type II interferons, leading to a marked increase in Ap 3 A, but not Ap 4 A [171, 172] . It has been proposed that this induction protects non-lymphoid cells from Trp depletion and the other effects of IDO1 expression by ensuring that sufficient Trp is diverted into protein synthesis for survival [173] . Enhanced WRS expression in T cells from patients with several autoimmune disorders is also believed to protect them from Trp depletion [72] . If this increased level of WRS were also to generate a significant amount of Ap 4 A, this would compromise the intended immunosuppression by downregulating Trp catabolism. Hence, WRS may have evolved a unique inability to make Ap 4 A. This also seems to confirm the physiological relevance of Ap 4 A as an important signaling molecule.