Analysis of the innate immune system through the ASK1-p38 MAP kinase pathway in mucosal immunity

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In this research, we first found that expression of constitutively active Drosophila ASK1 (DASK1) in flies upregulated melanin biosynthesis through the induction of tyrosine hydroxylase (TH) in a p38 pathway-dependent manner. We also found that p38-induced phosphorylation of NR4A nuclear factors was critically involved in the regulation of TH expression by DASK1. Moreover, p38-induced phosphorylation of NR4A nuclear factors operated also in mammalian cells. Taken together with the evidence showing the importance of melanin biosynthesis in Drosophila innate immunity, the regulation of NR4A factors by phosphorylation appears to play important roles in innate immune response through the ASK1-p38 pathway. On the other hand, we identified ASK2, which was highly homologous to ASK1, as a binding protein of ASK1. By forming a heteromeric complex with ASK1, ASK2 was found to escape from the proteolysis through proteasome and therefore stabilize. ASK2 functioned as a MAP3K that was potentially activated by oxidative stress only in the complex with ASK1. ASK2 was also found to induce ASK1 activation by direct phosphorylation, suggesting the existence of a mechanism by which ASK1 and ASK2 facilitate their activities to each other by distinct mechanisms. Since ASK2 expression was detected preferentially in the tissues including epithelium with relatively high turnover such as skin and gut, ASK2 may play pivotal roles in mucosal immunity as a regulator of the ASK1-p38 pathway.