RESUMO
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.
Assuntos
Cicatriz , Colágeno , Fibroblastos , Cicatrização , Peixe-Zebra , Humanos , Animais , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Colágeno/metabolismo , Cicatrização/efeitos dos fármacos , Cicatriz/metabolismo , Cicatriz/patologia , Cicatriz/tratamento farmacológico , Pele/metabolismo , Pele/patologia , Pele/efeitos dos fármacos , Fibrose , Peptídeos/farmacologia , Peptídeos/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacosRESUMO
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.