Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to InitiateDrosophilaNF-κB Signaling

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SUMMARYIn theDrosophilaimmune response, bacterial derived diaminopimelic acid-type peptidoglycan binds the receptors PGRP-LC and PGRP-LE, which through interaction with the adaptor protein Imd leads to activation of the NF-κB homolog Relish and robust antimicrobial peptide gene expression. PGRP-LC, PGRP-LE, and Imd each contain a motif with some resemblance to the RIP Homotypic Interaction Motif (RHIM), a domain found in mammalian RIPK proteins forming functional amyloids during necroptosis. Here we found that despite sequence divergence, theseDrosophilacryptic RHIMs formed amyloid fibrilsin vitroand in cells. Amyloid formation was required for signaling downstream of Imd, and in contrast to the mammalian RHIMs, was not associated with cell death. Furthermore, amyloid formation constituted a regulatable step and could be inhibited by Pirk, an endogenous feedback regulator of this pathway. Thus, diverse sequence motifs are capable of forming amyloidal signaling platforms, and the formation of these platforms may present a regulatory point in multiple biological processes.Graphical AbstractHighlightsFormation of functional Imd amyloid fibril is required for Drosophila NF-κB signalingCryptic RHIM motifs in peptidoglycan receptors PGRP-LC and PGRP-LE form amyloidsProtofibrils of PGRP-LC and PGRP-LE seed Imd amyloid polymerization via Imd cRHIMsPirk, an NF-κB target, acts as a feedback inhibitor of Imd amyloid formationKleino et al. show that amyloid formation is required for activation of the Drosophila Imd pathway upon recognition of bacterial peptidoglycans. Amyloid formation involves a motif resembling one found in necroptosis-associated mammalian proteins and can be negatively regulated, suggesting that amyloidal signaling platforms may present a regulatory point in multiple biological processes.

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