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.

Tryptophan catabolism. Canonical pathway analysis also shows that a number of metabolic pathways including tryptophan (Trp) catabolism, and consequently de novo NAD+ biosynthesis (derived from Trp [70] ), are strongly associated with the set of down-regulated genes (Fig 7 and S4 Table) while creatine phosphate biosynthesis, melatonin degradation (also a Trp derivative) and NAD+ phosphorylation are associated with the set of up-regulated genes. The strong down-regulation of both major pathways of Trp catabolism, particularly the key enzymes kynureninase (KYNU, 65-fold), indoleamine 2,3-dioxygenase (IDO1, 19-fold) and DOPA decarboxylase (Trp decarboxylase, DDC, 16-fold) is of particular note. Expression of the rate-limiting IDO1 is induced in myeloid-lineage cells by IFNs, particularly Type II, and TNF can act synergistically to increase IDO1 expression [71] , so the observed down-regulation of these pathways in NuKO cells combined with the moderate up-regulation of the negative effectors DAP12 (TYROBP) and BIN1, a tumor suppressor, (S3 Table) [72] would be expected to reduce IDO1 expression substantially.