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

Publication date: 17 October 2017
Source:Immunity, Volume 47, Issue 4
Author(s): Anni Kleino, Nancy F. Ramia, Gunes Bozkurt, Yanfang Shen, Himani Nailwal, Jing Huang, Johanna Napetschnig, Monique Gangloff, Francis Ka-Ming Chan, Hao Wu, Jixi Li, Neal Silverman
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.

Graphical abstract

Teaser

Kleino 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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