An Expanded Role for HLA Genes: HLA-B Encodes a microRNA that Regulates IgA and Other Immune Response Transcripts.
An Expanded Role for HLA Genes: HLA-B Encodes a microRNA that Regulates IgA and Other Immune Response Transcripts.
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DOI：
10.3389/fimmu.2017.00583
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发表时间：
2017
影响因子：
7.3
通讯作者：
Monos DS
中科院分区：
文献类型：
--
作者：
Chitnis N;Clark PM;Kamoun M;Stolle C;Brad Johnson F;Monos DS
我们描述了HLA-B基因座由其内含子编码的microRNA（miRNA），miR-6891- 5 p介导的一种新的功能作用。我们发现，miR-6891- 5 p的体外抑制影响了B淋巴母细胞样细胞系（B-LCL）考克斯中近200种转录物的表达，影响了大量的代谢途径，包括各种免疫反应网络。miR-6891- 5 p抑制后受影响最大的转录物是编码伊加重链的转录物。我们在免疫球蛋白重链α 1和2（IGHA 1和IGHA 2）转录物的3′UTR上鉴定了一个保守的miR-6891- 5 p靶位点，并证明该miRNA调节IGHA 1和IGHA 2的表达。与未受影响的家族成员相比，IgA缺陷患者的B-LCL表达的miR-6891- 5 p水平显著升高。在抑制miR-6891- 5 p后，IgA缺陷患者的B-LCL中伊加mRNA表达水平增加，伊加分泌恢复。这些发现表明miR-6891- 5 p在转录后水平调节IGHA 1和IGHA 2基因表达，并表明miR-6891- 5 p水平的增加可能有助于选择性伊加缺乏症的病因学。
We describe a novel functional role for the HLA-B locus mediated by its intron-encoded microRNA (miRNA), miR-6891-5p. We show that in vitro inhibition of miR-6891-5p impacts the expression of nearly 200 transcripts within the B-lymphoblastoid cell line (B-LCL) COX, affecting a large number of metabolic pathways, including various immune response networks. The top affected transcripts following miR-6891-5p inhibition are those encoding the heavy chain of IgA. We identified a conserved miR-6891-5p target site on the 3′UTR of both immunoglobulin heavy chain alpha 1 and 2 (IGHA1 and IGHA2) transcripts and demonstrated that this miRNA modulates the expression of IGHA1 and IGHA2. B-LCLs from IgA-deficient patients expressed significantly elevated levels of miR-6891-5p when compared with unaffected family members. Upon inhibition of miR-6891-5p, IgA mRNA expression levels were increased, and IgA secretion was restored in the B-LCL of an IgA-deficient patient. These findings indicate that miR-6891-5p regulates IGHA1 and IGHA2 gene expression at the posttranscriptional level and suggest that increase in miR-6891-5p levels may contribute to the etiology of selective IgA deficiency.