Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.
In the Drosophila immune 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, these Drosophila cryptic RHIMs formed amyloid fibrils in vitro and 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.
['Kleino|Anni|A|', 'Ramia|Nancy F|NF|', 'Bozkurt|Gunes|G|', 'Shen|Yanfang|Y|', 'Nailwal|Himani|H|', 'Huang|Jing|J|', 'Napetschnig|Johanna|J|', 'Gangloff|Monique|M|', 'Chan|Francis Ka-Ming|FK|', 'Wu|Hao|H|', 'Li|Jixi|J|', 'Silverman|Neal|N|']
D020816:Amino Acid Motifs D000595:Amino Acid Sequence D000682:Amyloid D000818:Animals D001665:Binding Sites D002352:Carrier Proteins D002460:Cell Line D029721:Drosophila Proteins D004331:Drosophila melanogaster D005260:Female D015870:Gene Expression D008297:Male D018613:Microscopy, Confocal D018448:Models, Immunological D009154:Mutation D016328:NF-kappa B D053422:Receptor-Interacting Protein Serine-Threonine Kinases D011956:Receptors, Cell Surface D020133:Reverse Transcriptase Polymerase Chain Reaction D017386:Sequence Homology, Amino Acid D015398:Signal Transduction
functional amyloid Imd NF-κB signaling PGRP-LC PGRP-LE RHIM innate immunity