Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapie...Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.展开更多
His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are as...His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are associated with interstitial lung disease, myositis, and morbidity. It is unknown whether the sequestration of HARS is an epiphenomenon or plays a causal role in the disease. Here, we show that HARS circulates in healthy individuals, but it is largely undetectable in the serum of anti-Jo-1-positive antisynthetase syndrome patients. In cultured primary human skeletal muscle myoblasts (HSkMC), HARS is released in increasing amounts during their differentiation into myotubes. We further show that HARS regulates immune cell engagement and inhibits CD4+ and CD8+ T-cell activation. In mouse and rodent models of acute inflammatory diseases, HARS administration downregulates immune activation. In contrast, neutralization of extracellular HARS by high-titer antibody responses during tissue injury increases susceptibility to immune attack, similar to what is seen in humans with anti-Jo-1-positive disease. Collectively, these data suggest that extracellular HARS is homeostatic in normal subjects, and its sequestration contributes to the morbidity of the anti-Jo-1-positive antisynthetase syndrome.展开更多
Abnormally enhanced de novo lipid biosynthesis has been increasingly realized to play crucial roles in the initiation and progression of varieties of cancers including breast cancer.However,the mechanisms underlying t...Abnormally enhanced de novo lipid biosynthesis has been increasingly realized to play crucial roles in the initiation and progression of varieties of cancers including breast cancer.However,the mechanisms underlying the dysregulation of lipid biosynthesis in breast cancer remain largely unknown.Here,we reported that seryl tRNA synthetase(SerRS),a key enzyme for protein biosynthesis,could translocate into the nucleus in a glucose-dependent manner to suppress key genes involved in the de novo lipid biosynthesis.In normal mammary gland epithelial cells glucose can promote the nuclear translocation of SerRS by increasing the acetylation of SerRS at lysine 323.In SerRS knock-in mice bearing acetylation-defective lysine to arginine mutation.展开更多
基金supported by grants from the STI2030-Major Projects(2021ZD0202501)the National Natural Science Foundation of China(NSFC)(82150003,91949104,and 31871022)+1 种基金Zhejiang Province NSFC(LY19H090135),the National Institutes of Health(NIH)(R35 GM139627)Open Project from the State Key Laboratory of Genetic Resources and Evolution of China(GREKF20-08).
文摘Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.
基金Supported in part by a Fellowship from the National Foundation for Cancer Research.
文摘His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are associated with interstitial lung disease, myositis, and morbidity. It is unknown whether the sequestration of HARS is an epiphenomenon or plays a causal role in the disease. Here, we show that HARS circulates in healthy individuals, but it is largely undetectable in the serum of anti-Jo-1-positive antisynthetase syndrome patients. In cultured primary human skeletal muscle myoblasts (HSkMC), HARS is released in increasing amounts during their differentiation into myotubes. We further show that HARS regulates immune cell engagement and inhibits CD4+ and CD8+ T-cell activation. In mouse and rodent models of acute inflammatory diseases, HARS administration downregulates immune activation. In contrast, neutralization of extracellular HARS by high-titer antibody responses during tissue injury increases susceptibility to immune attack, similar to what is seen in humans with anti-Jo-1-positive disease. Collectively, these data suggest that extracellular HARS is homeostatic in normal subjects, and its sequestration contributes to the morbidity of the anti-Jo-1-positive antisynthetase syndrome.
基金This work was supported by grants from the National Natural Science Foundation of China[81772974,81972882]Bilateral Inter-Governmental S&T Cooperation Project from Ministry of Science and Technology of China[SQ2018YFE010068]。
文摘Abnormally enhanced de novo lipid biosynthesis has been increasingly realized to play crucial roles in the initiation and progression of varieties of cancers including breast cancer.However,the mechanisms underlying the dysregulation of lipid biosynthesis in breast cancer remain largely unknown.Here,we reported that seryl tRNA synthetase(SerRS),a key enzyme for protein biosynthesis,could translocate into the nucleus in a glucose-dependent manner to suppress key genes involved in the de novo lipid biosynthesis.In normal mammary gland epithelial cells glucose can promote the nuclear translocation of SerRS by increasing the acetylation of SerRS at lysine 323.In SerRS knock-in mice bearing acetylation-defective lysine to arginine mutation.
