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Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation

Lee, Ernest Y. and Srinivasan, Yashes and de Anda, Jaime and Nicastro, Lauren K. and Tükel, Çagla and Wong, Gerard C. L. (2020) Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation. Frontiers in Immunology, 11 . Art. No. 1629. ISSN 1664-3224. PMCID PMC7412598. doi:10.3389/fimmu.2020.01629.

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Pathological self-assembly is a concept that is classically associated with amyloids, such as amyloid-β (Aβ) in Alzheimer's disease and α-synuclein in Parkinson's disease. In prokaryotic organisms, amyloids are assembled extracellularly in a similar fashion to human amyloids. Pathogenicity of amyloids is attributed to their ability to transform into several distinct structural states that reflect their downstream biological consequences. While the oligomeric forms of amyloids are thought to be responsible for their cytotoxicity via membrane permeation, their fibrillar conformations are known to interact with the innate immune system to induce inflammation. Furthermore, both eukaryotic and prokaryotic amyloids can self-assemble into molecular chaperones to bind nucleic acids, enabling amplification of Toll-like receptor (TLR) signaling. Recent work has shown that antimicrobial peptides (AMPs) follow a strikingly similar paradigm. Previously, AMPs were thought of as peptides with the primary function of permeating microbial membranes. Consistent with this, many AMPs are facially amphiphilic and can facilitate membrane remodeling processes such as pore formation and fusion. We show that various AMPs and chemokines can also chaperone and organize immune ligands into amyloid-like ordered supramolecular structures that are geometrically optimized for binding to TLRs, thereby amplifying immune signaling. The ability of amphiphilic AMPs to self-assemble cooperatively into superhelical protofibrils that form structural scaffolds for the ordered presentation of immune ligands like DNA and dsRNA is central to inflammation. It is interesting to explore the notion that the assembly of AMP protofibrils may be analogous to that of amyloid aggregates. Coming full circle, recent work has suggested that Aβ and other amyloids also have AMP-like antimicrobial functions. The emerging perspective is one in which assembly affords a more finely calibrated system of recognition and response: the detection of single immune ligands, immune ligands bound to AMPs, and immune ligands spatially organized to varying degrees by AMPs, result in different immunologic outcomes. In this framework, not all ordered structures generated during multi-stepped AMP (or amyloid) assembly are pathological in origin. Supramolecular structures formed during this process serve as signatures to the innate immune system to orchestrate immune amplification in a proportional, situation-dependent manner.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lee, Ernest Y.0000-0001-5144-2552
Wong, Gerard C. L.0000-0003-0893-6383
Additional Information:© 2020 Lee, Srinivasan, de Anda, Nicastro, Tükel and Wong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 01 May 2020; Accepted: 17 June 2020; Published: 31 July 2020. Author Contributions: All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. EL was supported by the Systems and Integrative Biology Training Program (NIH T32GM008185), the Medical Scientist Training Program (NIH T32GM008042), and the Dermatology Scientist Training Program (NIH T32AR071307) at UCLA. EL was also supported by an Early Career Research Grant from the National Psoriasis Foundation. JA was supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1650604. ÇT was supported by NIH AI137541, AI132996, AI148770, and AI151893. GW was supported by NIH R01AI143730, NIH R01AI052453, NSF DMR1808459, and the National Psoriasis Foundation 20194384. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding AgencyGrant Number
NIH Predoctoral FellowshipT32GM008185
NIH Predoctoral FellowshipT32GM008042
NIH Predoctoral FellowshipT32AR071307
National Psoriasis Foundation20194384
NSF Graduate Research FellowshipDGE-1650604
Department of Energy (DOE)DE-AC02-76SF00515
Subject Keywords:antimicrobial peptides, amyloids, self-assembly, Toll-like receptors, innate immunity, autoimmune diseases, neurodegenerative diseases
PubMed Central ID:PMC7412598
Record Number:CaltechAUTHORS:20200901-122741965
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Official Citation:Lee EY, Srinivasan Y, de Anda J, Nicastro LK, Tükel Ç and Wong GCL (2020) Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation. Front. Immunol. 11:1629. doi: 10.3389/fimmu.2020.01629
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105204
Deposited By: Tony Diaz
Deposited On:08 Sep 2020 19:46
Last Modified:16 Nov 2021 18:40

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