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1.
Nat Commun ; 15(1): 3302, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658535

RESUMEN

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.


Asunto(s)
Cicatriz , Colágeno , Fibroblastos , Cicatrización de Heridas , Pez Cebra , Humanos , Animales , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Colágeno/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Cicatriz/metabolismo , Cicatriz/patología , Cicatriz/tratamiento farmacológico , Piel/metabolismo , Piel/patología , Piel/efectos de los fármacos , Fibrosis , Péptidos/farmacología , Péptidos/metabolismo , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/patología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos
2.
Nat Biotechnol ; 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38195987

RESUMEN

Microorganisms can be equipped with synthetic genetic programs for the production of targeted therapeutic molecules. Cutibacterium acnes is the most abundant commensal of the human skin, making it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin, in vivo, for the modulation of cutaneous sebum production.

3.
Nat Commun ; 9(1): 3747, 2018 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-30217970

RESUMEN

Knowing which proteins and RNAs directly interact is essential for understanding cellular mechanisms. Unfortunately, discovering such interactions is costly and often unreliable. To overcome these limitations, we developed rec-YnH, a new yeast two and three-hybrid-based screening pipeline capable of detecting interactions within protein libraries or between protein libraries and RNA fragment pools. rec-YnH combines batch cloning and transformation with intracellular homologous recombination to generate bait-prey fusion libraries. By developing interaction selection in liquid-gels and using an ORF sequence-based readout of interactions via next-generation sequencing, we eliminate laborious plating and barcoding steps required by existing methods. We use rec-Y2H to simultaneously map interactions of protein domains and reveal novel putative interactors of PAR proteins. We further employ rec-Y2H to predict the architecture of published coprecipitated complexes. Finally, we use rec-Y3H to map interactions between multiple RNA-binding proteins and RNAs-the first time interactions between protein and RNA pools are simultaneously detected.


Asunto(s)
Mapas de Interacción de Proteínas , Proteínas de Unión al ARN/metabolismo , ARN/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Técnicas del Sistema de Dos Híbridos , Clonación Molecular , Secuenciación de Nucleótidos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento
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