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

Immunity. 2017 Oct 17;47(4):635-647.e6. doi: 10.1016/j.immuni.2017.09.011.

Abstract

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.

Keywords: Imd; NF-κB signaling; PGRP-LC; PGRP-LE; RHIM; functional amyloid; innate immunity.

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / immunology
  • Amino Acid Sequence
  • Amyloid / immunology*
  • Amyloid / metabolism
  • Animals
  • Binding Sites / genetics
  • Binding Sites / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Cell Line
  • Drosophila Proteins / genetics
  • Drosophila Proteins / immunology*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / immunology
  • Female
  • Gene Expression / immunology
  • Male
  • Microscopy, Confocal
  • Models, Immunological
  • Mutation
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Signal Transduction / immunology*

Substances

  • Amyloid
  • Carrier Proteins
  • Drosophila Proteins
  • NF-kappa B
  • Receptors, Cell Surface
  • imd protein, Drosophila
  • peptidoglycan receptor
  • peptidoglycan recognition protein
  • Receptor-Interacting Protein Serine-Threonine Kinases