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1.
Dis Model Mech ; 14(6)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085701

RESUMO

Heterozygous missense mutations in the human COL7A1 gene - coding for collagen VII - lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and - together with a relatively mild phenotype - represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.


Assuntos
Epidermólise Bolhosa Distrófica/genética , Mutação Puntual , Animais , Sistemas CRISPR-Cas , Colágeno Tipo VII/genética , Modelos Animais de Doenças , Humanos , Camundongos
2.
J Immunol ; 202(12): 3483-3492, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31061008

RESUMO

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2-/- mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2-/- mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo.


Assuntos
Infecções por Cardiovirus/imunologia , Citoplasma/metabolismo , Vírus da Encefalomiocardite/fisiologia , Endossomos/metabolismo , Herpes Simples/imunologia , Herpesvirus Humano 1/fisiologia , Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Animais , Células Cultivadas , DNA/imunologia , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Transporte de Nucleotídeos/genética , Poli I-C/imunologia , Transporte de RNA/genética
3.
Immunity ; 47(3): 498-509.e6, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28916264

RESUMO

Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and-in the case of EMCV and HSV-1-reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity.


Assuntos
Imunidade Inata , Proteínas de Membrana/metabolismo , Transporte de RNA , RNA de Cadeia Dupla/imunologia , RNA de Cadeia Dupla/metabolismo , Animais , Infecções por Cardiovirus/genética , Infecções por Cardiovirus/imunologia , Linhagem Celular , Citoplasma , Proteína DEAD-box 58/metabolismo , Modelos Animais de Doenças , Vírus da Encefalomiocardite/genética , Vírus da Encefalomiocardite/imunologia , Endossomos/metabolismo , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Lisossomos/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas de Transporte de Nucleotídeos , Ligação Proteica , Transporte Proteico , RNA Viral/genética , RNA Viral/metabolismo , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo
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