MALT-1 mediates IL-17 neural signaling to regulate\xa0C. elegans behavior, immunity and longevity

Sean M Flynn,Murat Artan,Farida Begum,Mario de Bono,Alastair Crisp,Geoffrey M Nelson,Stephen Barratt,Sew-Yeu Peak-Chew,Changchun Chen,Mark Skehel

doi:10.1038/s41467-020-15872-y

Abstract

Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate IL-17 signaling in neurons, and the extent it can alter organismal phenotypes. We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans neurons. We identify the paracaspase MALT-1 as a critical output of the pathway. MALT1 mediates signaling from many immune receptors in mammals, but was not previously implicated in IL-17 signaling or nervous system function. C. elegans MALT-1 forms a complex with homologs of Act1 and IRAK and appears to function both as a scaffold and a protease. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17–MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural circuit function downstream of IL-17 to remodel physiology and behavior.

Highlights

Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function
We report that IL-17 signaling in the C. elegans nervous system is mediated by the paracaspase MALT-1
We find that C. elegans MALT-1 is expressed throughout the nervous system and forms an in vivo complex with IL-17 signaling components, namely the C. elegans homologs of Act[1], IRAK and IκBζ/IκBNS

Summary

Introduction

Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17–MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Immune signaling pathways can regulate the development and function of the nervous system in both health and disease[1,2,3]. Many of these effects are mediated by cytokines, small, secreted proteins that can participate in neuroimmune and interneuronal communication. In a rodent model of infection during pregnancy, IL-17 secretion during maternal immune activation drives autism-related behaviors in the pups[13] This phenotype is associated with hyperactivity of a specific cortical sub-region that expresses IL-17 receptors (IL-17R)[14]. Defects in IL-17/MALT-1 signaling lead to reconfigured gene expression, and changes in behavior and physiology, including altered immunity and extended lifespan

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Conclusion