Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-kappaB Signaling
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Pathology
Immunity | Immunology of Infectious Disease
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-kappaB 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.
md, NF-κB signaling, PGRP-LC, PGRP-LE, RHIM, functional amyloid, innate immunity
DOI of Published Version
Kleino A, Ramia NF, Bozkurt G, Shen Y, Nailwal H, Huang J, Napetschnig J, Gangloff M, Chan FK, Wu H, Li J, Silverman N. 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. PMID: 29045898; PMCID: PMC5665175. Link to article on publisher's site
Kleino A, Ramia NF, Bozkurt G, Shen Y, Nailwal H, Huang J, Napetschnig J, Gangloff M, Chan FK, Wu H, Li J, Silverman NS. (2017). Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-kappaB Signaling. Infectious Diseases and Immunology Publications. https://doi.org/10.1016/j.immuni.2017.09.011. Retrieved from https://escholarship.umassmed.edu/infdis_pp/436