ABSTRACT
Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.
Subject(s)
Aspartic Acid , Caspase 6 , Coronavirus Infections , Coronavirus , Cysteine , Host-Pathogen Interactions , Virus Replication , Animals , Apoptosis , Aspartic Acid/metabolism , Caspase 6/metabolism , Coronavirus/growth & development , Coronavirus/pathogenicity , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Cricetinae , Cysteine/metabolism , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Humans , Interferons/antagonists & inhibitors , Interferons/immunology , Lung/pathology , Mesocricetus , Mice , Middle East Respiratory Syndrome Coronavirus , Severe acute respiratory syndrome-related coronavirus , SARS-CoV-2 , Survival Rate , Weight LossABSTRACT
Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.
Subject(s)
Carrier Proteins , Cell Polarity , Membrane Proteins , Spine , Zebrafish , Animals , Zebrafish/genetics , Zebrafish/embryology , Humans , Mice , Cell Polarity/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Spine/abnormalities , Spine/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism , Scoliosis/genetics , Scoliosis/congenital , Scoliosis/metabolism , Wnt Signaling Pathway/genetics , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , FemaleABSTRACT
Er-xian Decoction (EXD), containing Herba epimedii Maxim (HEP) and Curculigo orchioides Gaertn (XM) as principal drugs, is a traditional Chinese medicine (TCM) formula prescribed for the treatment of postmenopausal osteoporosis. In the present study, the in vivo anti-osteoporosis effects of EXD, HEP and XM on four-month-old ovariectomized (OVX) Sprague-Dawley rats were investigated. Micro-computed tomography analysis showed that EXD could significantly improve the micro-architectural parameters (BMD, BV/TV, Tb.N, Tb.Th, and Tb.Sp) of trabecular bone in the distal femur and proximal tibia in OVX rats (p < 0.05). The biomechanical parameters of the distal femur in rats treated with EXD were also improved significantly (p < 0.05 vs. OVX group). The in vivo efficacy of EXD was found to be superior to HEP or XM alone in improving the bone properties of OVX rats. Treatment of rat osteoblastic-like UMR-106 cells with EXD, HEP, and XM significantly promoted the cell proliferation rate (p < 0.05) with the most promising effects observed in cells treated with EXD (p < 0.001). The proliferative effect in UMR-106 cells induced by EXD, HEP, and XM were abolished in the presence of the estrogen antagonist, ICI182780, suggesting that their effects were mediated by estrogen receptor (ER). Additionally, EXD could activate ER-α and ER-ß mediated estrogen-response element (ERE)-dependent luciferase activity as well as phosphorylate ER-α at serine 118 in UMR-106 cells. Taken together, EXD offered better osteoprotective effects than its single principal herb, and the beneficial effects of EXD in preventing bone deteriorations are, at least partially, through the ER signaling pathway.