Inflammatory bowel disease(IBD)is a formidable disease due to its complex pathogenesis.Macrophages,as a major immune cell population in IBD,are crucial for gut homeostasis.However,it is still unveiled how macrophages ...Inflammatory bowel disease(IBD)is a formidable disease due to its complex pathogenesis.Macrophages,as a major immune cell population in IBD,are crucial for gut homeostasis.However,it is still unveiled how macrophages modulate IBD.Here,we found that LIM domain only 7(LMO7)was downregulated in pro-inflammatory macrophages,and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)through K48-mediated ubiquitination in macrophages.As an enzyme that regulates glycolysis,PFKFB3 degradation led to the glycolytic process inhibition in macrophages,which in turn inhibited macrophage activation and ultimately attenuated murine colitis.Moreover,we demonstrated that PFKFB3 was required for histone demethylase Jumonji domaincontaining protein 3(JMJD3)expression,thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27(H3K27me3).Overall,our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis.Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.展开更多
Background: Congenital idiopathic clubfoot is a very common musculoskeletal birth defect, but with no known etiology. Dietz et al. have shown possible linkage in chromosome 3 and 13 in a large, multigenerational famil...Background: Congenital idiopathic clubfoot is a very common musculoskeletal birth defect, but with no known etiology. Dietz et al. have shown possible linkage in chromosome 3 and 13 in a large, multigenerational family with congenital idiopathic clubfoot. Current evidence suggests that muscle development is impaired in patients with congenital idiopathic club-foot, therefore we hypothesized that mutations in genes related to muscle development could be associated with this deformity. From the areas identified in the linkage study, candidate genes SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 were selected based upon their presence in skeletal muscle as well as their involvement in muscle development. Methods: The exons and splice sites of the five genes were screened via sequence-based analysis in a group of 24 patients with congenital idiopathic clubfoot. All single nucleotide polymorphisms (SNPs) found were compared to public databases to determine allelic frequency and amino acid modification. Results: While many SNPs were found, none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. The SNPs found were shown to be common amongst a non-clubfoot population and to follow the allelic frequency of the general population. Conclusions: Based upon these results, SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 are not likely to be the major causes of congenital idiopathic clubfoot. Given the complexity of myogenesis, many other candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic club-foot. Clinical Relevance: This study further identifies genes which are unlikely to be the direct cause of congenital idiopathic clubfoot. It also helps to eliminate suspected genes found within the given bounds of chromosome 3 and 13.展开更多
基金supported by grants from the National Natural Science Foundation of China(82373875,82173821,81973329,82273934,82073858,82104186).
文摘Inflammatory bowel disease(IBD)is a formidable disease due to its complex pathogenesis.Macrophages,as a major immune cell population in IBD,are crucial for gut homeostasis.However,it is still unveiled how macrophages modulate IBD.Here,we found that LIM domain only 7(LMO7)was downregulated in pro-inflammatory macrophages,and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)through K48-mediated ubiquitination in macrophages.As an enzyme that regulates glycolysis,PFKFB3 degradation led to the glycolytic process inhibition in macrophages,which in turn inhibited macrophage activation and ultimately attenuated murine colitis.Moreover,we demonstrated that PFKFB3 was required for histone demethylase Jumonji domaincontaining protein 3(JMJD3)expression,thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27(H3K27me3).Overall,our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis.Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.
文摘Background: Congenital idiopathic clubfoot is a very common musculoskeletal birth defect, but with no known etiology. Dietz et al. have shown possible linkage in chromosome 3 and 13 in a large, multigenerational family with congenital idiopathic clubfoot. Current evidence suggests that muscle development is impaired in patients with congenital idiopathic club-foot, therefore we hypothesized that mutations in genes related to muscle development could be associated with this deformity. From the areas identified in the linkage study, candidate genes SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 were selected based upon their presence in skeletal muscle as well as their involvement in muscle development. Methods: The exons and splice sites of the five genes were screened via sequence-based analysis in a group of 24 patients with congenital idiopathic clubfoot. All single nucleotide polymorphisms (SNPs) found were compared to public databases to determine allelic frequency and amino acid modification. Results: While many SNPs were found, none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. The SNPs found were shown to be common amongst a non-clubfoot population and to follow the allelic frequency of the general population. Conclusions: Based upon these results, SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 are not likely to be the major causes of congenital idiopathic clubfoot. Given the complexity of myogenesis, many other candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic club-foot. Clinical Relevance: This study further identifies genes which are unlikely to be the direct cause of congenital idiopathic clubfoot. It also helps to eliminate suspected genes found within the given bounds of chromosome 3 and 13.
