RESUMO
Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin-1-dependent manner. ER-anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury-induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin-triggered pulmonary fibrosis in vivo. These findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.
Assuntos
Autoantígenos/metabolismo , Colágeno/antagonistas & inibidores , Cirrose Hepática/prevenção & controle , Fibrose Pulmonar/prevenção & controle , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Ribonucleoproteínas/metabolismo , Animais , Bleomicina , Tetracloreto de Carbono , Células Cultivadas , Colágeno/biossíntese , Colágeno/genética , Retículo Endoplasmático/metabolismo , Fibroblastos/metabolismo , Membranas Intracelulares/metabolismo , Isoproterenol , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Ligação Proteica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Antígeno SS-BRESUMO
As a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is involved in mitogen-activated protein kinase (MAPK) signaling pathway and contributes to immune surveillance via programmed cell death pathway (PD-1/PD-L1). To date, numerous SHP2 inhibitors have been developed, some of them have advanced into clinical trials. Moreover, the first PROTAC degrader SHP2-D26 has been proved to effectively induce degradation of SHP2, which may open a new avenue for targeted SHP2 therapies. In this review, we systematically summarized the development of SHP2 inhibitors with a particular focus on the structure-activity relationships (SAR) studies, crystal structures or binding models, and their modes of action.