Review Functional Reciprocity of Amyloids & Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation…, 2020

[SNT Gatchaman]

Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation
Lee EY; Srinivasan Y; de Anda J; Nicastro LK; Tükel Ç; Wong GCL;

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.

Link | PDF (Frontiers in immunology)

 

[SNT Gatchaman]

Posting as a background reference for Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes (2024, Proceedings of the National Academy of Sciences)

 

[SNT Gatchaman]

Amyloids and antimicrobial peptides (AMPs) are two classes of proteins that have fascinating biophysical and structural properties. Until recently, they were thought to be distinct entities with vastly different functions. Amyloids were strictly pathologic and accumulation in tissues invariably led to diseases. In comparison, AMPs are considered essential components of the innate immune system, defending against invasive microbial infections and sounding the alarm to activate cellular mediated immune responses.

AMPs and amyloids have strikingly similar structural and biophysical properties that enable them to self-assemble with immune ligands like DNA to amplify immune responses. Surprisingly, many amyloids possess hidden antimicrobial activity in addition to their known cytotoxic properties, suggesting a potential endogenous role in host defense.

AMPs are part of an ancient arm of the innate immune system that represents the first line of defense against microbial infections. AMPs [...] can be broadly categorized by their secondary structures: the α-helical AMPs, β-sheet AMPs, AMPs with cross α-β structures, and extended linear peptides with specific enriched amino acids. The prototypical human AMP is cathelicidin (LL37), which is an α-helical AMP with essential anti-infective and immunomodulatory functions. Prototypical human β-sheet AMPs are the defensins.

 

[SNT Gatchaman]

Amyloids constitute a broad class of proteins that have the unique ability to aggregate into fibrils with characteristic secondary structures. The structural, physicochemical, and biological properties of AMPs are similar to those of many amyloid proteins. The majority of amyloids have a β-sheet secondary structure, but recently a subset of α-helical amyloids was identified. Amyloids can be broadly categorized into those of eukaryotic and prokaryotic origins. Human endogenous amyloids are associated with over 50 distinct disease processes, the most famous of which is amyloid β-peptide (Aβ) in Alzheimer’s disease (AD). More and more proteins are being discovered to have amyloidogenic properties. Whether amyloids play a causal role in disease or are merely a consequence of disease is hotly debated.

The potential protective effects of host-generated amyloids have only recently emerged despite recognition of the association between chronic bacterial infections and amyloidosis for nearly a century.

Parkinson’s disease (PD)-associated α-synuclein has been long-studied as a model system for amyloid-mediated cytotoxicity [...]. Recently, it was shown to be antimicrobial against a variety of bacteria and fungi suggesting a potential endogenous role in host defense. In human patients with chronic gut inflammation, α-synuclein was found to be upregulated in enteric neurons, a fascinating finding given that PD often begins in the gut as constipation before neurologic symptoms appear.

 

[SNT Gatchaman]

AMPs, which were thought of as only having antimicrobial function, are now known to modulate innate immune receptors by forming amyloid-like protofibrils and scaffolding canonical immune ligands like DNA and RNA into geometrically organized patterns. Recognition of these complexes by the immune system drives autoimmunity in diseases like lupus, psoriasis, and scleroderma.

the revolutionary work demonstrating that Aβ, which has no known primary function, is an AMP that protects the nervous system against bacterial and fungal infections fundamentally challenges our view of endogenous human amyloids as solely pathologic.