RIOK-1 Is a Suppressor of the p38 MAPK Innate Immune Pathway in Caenorhabditis elegans .

Innate immunity is the primary defense mechanism against infection in metazoans. However, aberrant upregulation of innate immune-signaling pathways can also be detrimental to the host. The p38 MAPK/PMK-1 innate immune-signaling pathway has been demonstrated to play essential roles in cellular defenses against numerous infections in metazoans, including Caenorhabditis elegans . However, the negative regulators that maintain the homeostasis of this important innate immune pathway remain largely understudied. By screening a focused RNAi library against the kinome of C. elegans , we identified RIOK-1, a human RIO kinase homolog, as a novel suppressor of the p38 MAPK/PMK-1 signal pathway. We demonstrated that the suppression of riok-1 confers resistance to Aeromonas dhakensis infection in C. elegans . Using quantitative real time-PCR and riok-1 reporter worms, we found the expression levels of riok-1 to be significantly upregulated in worms infected with A. dhakensis . Our genetic epistasis analysis suggested that riok-1 acts on the upstream of the p38 MAPK/ pmk-1 genetic pathway. Moreover, the suppression of riok-1 enhanced the p38 MAPK signal, suggesting that riok-1 is a negative regulator of this innate pathway in C. elegans . Our epistatic results put riok-1 downstream of skn-1 , which encodes a p38 MAPK downstream transcription factor and serves as a feedback loop to the p38 MAPK pathway during an A. dhakensis infection. In conclusion, riok-1 is proposed as a novel innate immune suppressor and as a negative feedback loop model involving p38 MAPK, SKN-1, and RIOK-1 in C. elegans .