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

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

Author information

1
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Pathology, Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
4
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
5
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
6
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
7
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: wu@crystal.harvard.edu.
8
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: lijixi@fudan.edu.cn.
9
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: neal.silverman@umassmed.edu.

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

PMID:
29045898
PMCID:
PMC5665175
DOI:
10.1016/j.immuni.2017.09.011
[Indexed for MEDLINE]
Free PMC Article

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