Referencia

PMID: 23133388 doi: 10.1371/journal.ppat.1003005

Autores

Marc Torrent, David Pulido, Maria VictòriaNogués, Ester Boix.

Resumen

Antimicrobial proteins and peptides (AMPs) are important effectors of the innate immune system that play a vital role in the prevention of infections. Recent advances have highlighted the similarity between AMPs and amyloid proteins. Using the Eosinophil Cationic Protein as a model, we have rationalized the structure-activity relationships between amyloid aggregation and antimicrobial activity. Our results show how protein aggregation can induce bacteria agglutination and cell death. Using confocal and total internal reflection fluorescence microscopy we have tracked the formation in situ of protein amyloid-like aggregates at the bacteria surface and on membrane models. In both cases, fibrillar aggregates able to bind to amyloid diagnostic dyes were detected. Additionally, a single point mutation (Ile13 to Ala) can suppress the protein amyloid behavior, abolishing the agglutinating activity and impairing the antimicrobial action. The mutant is also defective in triggering both leakage and lipid vesicle aggregation. We conclude that ECP aggregation at the bacterial surface is essential for its cytotoxicity. Hence, we propose here a new prospective biological function for amyloid-like aggregates with potential biological relevance.

Descripción

Las infecciones bacterianas están clasificadas como enfermedades graves que causan millones de muertes al año en todo el mundo. Los antibióticos son fármacos efectivos contra este tipo de infecciones pero, desafortunadamente, los microorganismos están desarrollando mecanismos de resistencia a una velocidad alarmante. Es por esta razón que las proteínas y péptidos propios del sistema inmunitario innato están captandointerésen el desarrollo de fármacos alternativos. Entre estas proteínas se encuentra la Proteína Catiónica de Eosinófilos (ECP), proteína secretada por los eosinófilos en los focos de infección, que presenta una elevadaactividad antimicrobiana y una capacidad excepcional de aglutinar las células bacterianas. En este artículo mostramos como el mecanismo de aglutinación de la ECP está basado en la agregación amiloideade la proteína en la superficie de las bacterias. Estas observaciones establecen un nuevo paradigma de cómo la naturaleza puede utilizar los agregados de tipo amiloideo para combatir las infecciones bacterianas. Los resultados presentados en este artículo no solo nos pueden servir para entender mejor la relación entre los mecanismos infecciosos y las enfermedades neurodegenerativas sino también para inspirar el desarrollo de nuevos fármacos basados en proteínas y péptidosantimicrobianos.

imagen junio

REFERENCIA DEL GRUPO INVESTIGADOR

Las ribonucleasas humanas forman parte del sistema inmunitario innato y son modelos interesantes para el desarrollo de fármacos alternativos para el tratamiento de infecciones y problemas inflamatorios.Nuestro grupo investiga, principalmente, el mecanismo de acción antimicrobiano de lasribonucleasashumanas, especialmente la Proteína Catiónica de Eosinófilos (ECP) y la ribonucelasa de piel (o Ribonucleasa 7). En este contexto, pretendemos caracterizar las relaciones estructura-función de estas ribonucleasas para identificar sus dominios funcionales y aplicar nuestros descubrimientos al desarrollo de nuevos agentes antimicrobianos.

Para ver el artículo completo, pulse aqui

Más artículos en la revista SEBBM.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Read more

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Read more

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß after myocardial infarction

01-12-2020

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood...

Read more

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

30-10-2020

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic...

Read more

Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

01-10-2020

C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins...

Read more

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

31-08-2020

The reciprocal translocation t(12;21)(p13;q22)[ETV6/RUNX1] is the most frequent chromosomal rearrangement in pediatric B-cell acute lymphoblastic leukemia(B-ALL). Long non-coding RNAs (lncRNAs) play important roles in numerous diseases and they represent an...

Read more

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Read more

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

01-07-2020

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism...

Read more

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Read more

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Read more

Protector Members