CELL RESEARCH
·
2017
·Vol. 28
·期 1
·48-68
·
IF 15.606
Xu Xingxing,Li Chuanyin,Gao Xiaobo,Xia Kun,Guo Hui,Li Yali,Hao Zijian,Zhang Lei,Gao Daming,Xu Chenfan,Xu Huatai,Xiong Zhi-Qi,Qiu Zilong,Mei Ling,Xie Xiaoduo,Ruan Kangcheng,Hu Ronggui
The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.
研究领域:
神经科学
·
分子生物学
·
遗传学
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DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2024
·
IF 4.1
Huaxing Su,Yitong Zhang,Zhongwei He,Yucong Yang,Yuqin Ren,Wei Cao,Yufeng Liu,Jiangong Ren,Yufen Wang,Guixing Wang,Chunguang Gong,Jilun Hou
Ube3a is a member of the E3 ubiquitin ligase HECTc family, and its role has been established in neurodevelopmental disorders. However, studies on its role in Japanese flounder are scarce. Thus, in this study, the ube3a of Japanese flounder was cloned, and its role in conferring resistance against Chinook salmon bafnivirus (CSBV) was analyzed. Japanese flounder ube3a encoded a protein containing 834 amino acids. Interestingly, its homology with the Atlantic halibut was determined to be 94%. In addition, there were differential expressions of ube3a in different tissues of Japanese flounder, with the highest expression level observed in the fin, followed by the gills and skin ( P ≤ 0.05). Subcellular localization analysis revealed that Ube3a is a cytoplasmic protein. We established an in vitro CSBV infection model using Japanese flounder gill cell line (FG). After ube3a overexpression, the viral load was significantly lower than that of the control group ( P ≤ 0.05). Contrastingly, after incubation of FG cells with an E3 ubiquitin ligase inhibitor, the viral load was significantly higher than in the control group ( P ≤ 0.01). Then, the expression levels of nf-κb , traf3 , and tnf-α after incubation with an E3 ubiquitin ligase inhibitor were examined. The results demonstrated that ube3a may exerted a significant antiviral effect in Japanese flounder via the ubiquitination pathway.
研究领域:
分子生物学
·
免疫学
·
病毒学
·
渔业科学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yunfei Li,Cheng Cheng,Mingfei Li,Yi Hou,Jie Li,Shichao Duan,Enyi Gao,Ke Liu,Zhipeng Dai
Osteoarthritis (OA) is a common degenerative joint disease. Cysteine-rich intestinal protein 1(CRIP1) is involved in many biological processes, but its role in OA remains unclear. OA-related datasets from the GEO database revealed that CRIP1 expression was upregulated in OA patient cartilage. This upregulation was also confirmed in our collected clinical samples and OA mice. CRIP1 knockdown increased the expression of collagen II and tissue inhibitor of metalloproteinases 3, but reduced the levels of matrix metalloproteinase 13 and phosphorylated p65 in IL-1β-induced primary mouse chondrocytes. In contrast, CRIP1 overexpression had the opposite effects. CRIP1 knockdown alleviated cartilage damage, reduced extracellular matrix (ECM) degradation, and inhibited p65 phosphorylation in OA mice. To investigate the CRIP1 mechanism in OA, proteins regulated by CRIP1 were screened by label-free quantitative proteomics, and the milk fat globule-epidermal growth factor 8 (MFGE8) protein was identified in the search for CRIP1-specific binding proteins in chondrocytes using immunoprecipitation/mass spectrometry. CRIP1 knockdown increased MFGE8 expression in OA mouse cartilage and IL-1β-induced chondrocytes. CRIP1 overexpression resulted in a shortened half-life of MFGE8 in chondrocytes. The proteasome inhibitor reversed the MFGE8 downregulation in CRIP1 overexpressing chondrocytes. Immunoprecipitation and rescue experiments verified that CRIP1 regulated MFGE8 degradation by promoting its binding to E3 ubiquitin-protein ligase 3A (UBE3A). Meanwhile, CRIP1 affected ECM degradation and NF-κB pathway through MFGE8. In summary, CRIP1 knockdown attenuated cartilage damage in OA mice and inhibited the ECM degradation and p65 activation in vivo and in vitro . This effect may be mediated by inhibiting the interaction between UBE3A and MFGE8.
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PubMed
高影响因子
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