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Human Pentraxins Bind to Misfolded Proteins and Inhibit Production of Type I Interferon Induced by Nucleic Acid-Containing Amyloid.

ABSTRACT: Objective:Amyloid deposition is linked to multiple human ailments, including neurodegenerative diseases, type 2 diabetes, and systemic amyloidosis. The assembly of misfolded proteins into amyloid fibrils involves an intermediate form, i.e., soluble amyloid precursor (AP), which exerts cytotoxic function. Insoluble amyloid also stimulates innate immune cells to elicit cytokine response and inflammation. How any of these misfolded proteins are controlled by the host remains obscure. Serum amyloid-P component (SAP) is a universal constituent of amyloid deposits. Short-chain pentraxins, which include both SAP and C-reactive protein (CRP), are pattern recognition molecules that bind to diverse ligands and promote the clearance of microbes and cell debris. Whether these pentraxins interact with AP and cofactor-containing amyloid and subsequently impact their function is not known. Methods and Results:To detect the interaction between SAP and different types of amyloids, we performed dot blot analysis. The results showed that SAP invariably bound to protein-only, nucleic acid-containing and glycosaminoglycan-containing amyloid fibrils. This interaction required the presence of calcium. By ELISA, both SAP and CRP bound to soluble AP in the absence of divalent cations. Further characterization, by gel filtration, implied that SAP decamer may recognize AP whereas aggregated SAP preferentially associates with amyloid fibril. Although SAP binding did not affect cytotoxic function of AP, SAP potently inhibited the production of interferon-? from human plasmacytoid dendritic cells triggered by DNA-containing amyloid. Conclusions:Our data suggest that short pentraxins differentially interact with various forms of misfolded proteins and, in particular, modulate the ability of nucleic acid-containing amyloid to stimulate aberrant type I interferon response. Hence, pentraxins may function as key players in modulating the pathogenesis of protein misfolding diseases as well as interferon-mediated autoimmune manifestation.

SUBMITTER: Dorta-Estremera SM

PROVIDER: S-EPMC6510259 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Human Pentraxins Bind to Misfolded Proteins and Inhibit Production of Type I Interferon Induced by Nucleic Acid-Containing Amyloid.

Dorta-Estremera Stephanie M SM Cao Wei W

Journal of clinical & cellular immunology 20150623 3

<h4>Objective</h4>Amyloid deposition is linked to multiple human ailments, including neurodegenerative diseases, type 2 diabetes, and systemic amyloidosis. The assembly of misfolded proteins into amyloid fibrils involves an intermediate form, <i>i.e.</i>, soluble amyloid precursor (AP), which exerts cytotoxic function. Insoluble amyloid also stimulates innate immune cells to elicit cytokine response and inflammation. How any of these misfolded proteins are controlled by the host remains obscure. ...[more]

PMID: 31080694

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Project description:UnlabelledArenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens.ImportanceWe show that all known human-pathogenic arenaviruses share an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our report provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions.

Dataset Information

Human Pentraxins Bind to Misfolded Proteins and Inhibit Production of Type I Interferon Induced by Nucleic Acid-Containing Amyloid.

Publications

Human Pentraxins Bind to Misfolded Proteins and Inhibit Production of Type I Interferon Induced by Nucleic Acid-Containing Amyloid.

Similar Datasets

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