The IL-17 pathway intertwines with neurotrophin and TLR/IL-1R pathways since its domain shuffling origin

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-05, Vol.121 (19), p.e2400903121
• Main Authors: Chen, Shenghui, Fan, Huiping, Ran, Chenrui, Hong, Yun, Feng, Huixiong, Yue, Zirui, Zhang, Hao, Pontarotti, Pierre, Xu, Anlong, Huang, Shengfeng
• Format: Article
• Language: English
• Subjects: Activator protein 1; Adaptive immunology; Adaptor proteins; Animals; Biological Sciences; Cephalochordata; Crustaceans; Danio rerio; Death; Evolution, Molecular; Immunology; Insects; Interleukin 1 receptors; Interleukin 17; Interleukin-17 - metabolism; Kinases; Larvae; Life Sciences; MAP kinase; Molting; Mortality; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; NF-κB protein; Proteins; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - metabolism; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - metabolism; Redesign; Sex differentiation; Sex hormones; Signal Transduction; Toll-like receptors; Toll-Like Receptors - metabolism; Torso; Transcription factors; Tyrosine; Zebrafish
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2400903121

The IL-17 pathway displays remarkably diverse functional modes between different subphyla, classes, and even orders, yet its driving factors remains elusive. Here, we demonstrate that the IL-17 pathway originated through domain shuffling between a Toll-like receptor (TLR)/IL-1R pathway and a neurotrophin-RTK (receptor-tyrosine-kinase) pathway (a Trunk-Torso pathway). Unlike other new pathways that evolve independently, the IL-17 pathway remains intertwined with its donor pathways throughout later evolution. This intertwining not only influenced the gains and losses of domains and components in the pathway but also drove the diversification of the pathway's functional modes among animal lineages. For instance, we reveal that the crustacean female sex hormone, a neurotrophin inducing sex differentiation, could interact with IL-17Rs and thus be classified as true IL-17s. Additionally, the insect prothoracicotropic hormone, a neurotrophin initiating ecdysis in by binding to Torso, could bind to IL-17Rs in other insects. Furthermore, IL-17R and TLR/IL-1R pathways maintain crosstalk in amphioxus and zebrafish. Moreover, the loss of the Death domain in the pathway adaptor connection to IκB kinase and stress-activated protein kinase (CIKSs) dramatically reduced their abilities to activate nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) in amphioxus and zebrafish. Reinstating this Death domain not only enhanced NF-κB/AP-1 activation but also strengthened anti-bacterial immunity in zebrafish larvae. This could explain why the mammalian IL-17 pathway, whose CIKS also lacks Death, is considered a weak signaling activator, relying on synergies with other pathways. Our findings provide insights into the functional diversity of the IL-17 pathway and unveil evolutionary principles that could govern the pathway and be used to redesign and manipulate it.