E3 Ubiquitin Ligase March1 Facilitates OX40L Expression in Allergen-Stimulated Dendritic Cells Through Mediating the Ubiquitination of HDAC11.
E3 Ubiquitin Ligase March1 Facilitates OX40L Expression in Allergen-Stimulated Dendritic Cells Through Mediating the Ubiquitination of HDAC11.
复制标题
E3 泛素连接酶 March1 通过介导 HDAC11 泛素化促进过敏原刺激的树突状细胞中 OX40L 的表达
DOI：
10.2147/jaa.s318104
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发表时间：
2021
影响因子：
3.2
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Zhang X;Sun Z;Guo S;Zhang J;Gu W;Chen Z;Huang L
背景研究表明，膜相关RING-CH 1（March 1）在哮喘发病中可能起重要作用。方法分别采用qRT-PCR和Western blot方法检测mRNA和蛋白水平。采用免疫荧光法检测March 1与HDAC 11是否共定位。进行免疫共沉淀以检查蛋白质的组合。荧光素酶法检测基因启动子活性。结果哮喘儿童和哮喘动物的DC中March 1和OX 40配体（OX 40 L）的mRNA和蛋白水平均升高。组蛋白去乙酰化酶11（HDAC 11）蛋白在哮喘患儿和哮喘模型DC中表达减少。March 1的增加或减少只在蛋白水平上影响HDAC 11的表达。此外，HDAC 11的增加可抑制屋尘螨（HDMs）处理的DC中OX 40 L的表达，而HDAC 11的减少可促进OX 40 L的表达。HDAC 11的增加显著逆转了March 1对OX 40 L表达的促进作用。我们的数据进一步证明March 1通过诱导泛素化和降解降低HDAC 11的蛋白水平。HDAC 11联合KLF 4降低OX 40 L基因启动子活性，从而下调OX 40 L水平。结论HDAC 11可促进KLF 4依赖性OX 40 L的表达。March 1通过促进HDAC 11的泛素化和降解，进而阻断HDAC 11对OX 40 L的抑制，从而促进OX 40 L的表达。
Background It was demonstrated that membrane-associated RING-CH 1 (March 1) might play an important role in the pathogenesis of asthma. Methods The levels of mRNA and protein were measured by qRT-PCR and Western blot, respectively. Immunofluorescence assay was used to determine whether March1 co-locates with HDAC11. Co-immunoprecipitation was performed to examine the combination of proteins. Moreover, luciferase assay was used to measure the promoter activity of genes. Results The mRNA and protein levels of both March1 and OX40 ligand (OX40L) were increased in the dendritic cells (DCs) from asthmatic children and asthmatic animals. Histone deacetylase 11 (HDAC11) protein was decreased in the DCs from asthmatic children and asthmatic model. Increasing of March1 or decreasing of March1 only affect the expression of HDAC11 in protein level. Besides, increasing of HDAC11 could inhibit OX40L expression, and decreasing of HDAC11 promoted OX40L expression in house dust mites (HDMs)-treated DCs. Increasing of HDAC11 notably reversed the promotion of March1 to OX40L expression. Our data further proved that March1 reduced the protein level of HDAC11 through inducing ubiquitination and degradation. HDAC11 combined with krüppel‐like factor 4 (KLF4) to decrease the activity of OX40L gene promoter, thus to downregulate the level of OX40L. Conclusion Overall, our data showed that HDAC11 promoted KLF4-dependent OX40L decreasing. However, March1 promoted OX40L expression through enhancing the ubiquitination and degradation of HDAC11 and subsequent blocking the inhibition of HDAC11 to OX40L.