Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response
Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response
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DOI：
10.1074/jbc.m110.134106
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Corvera, Silvia
中科院分区：
文献类型：
--
作者：
Burkart, Alison;Shi, Xiarong;Corvera, Silvia
未折叠蛋白反应（UPR）是一种平衡内质网（ER）蛋白质折叠能力和细胞分泌蛋白负荷的稳态信号机制。内质网蛋白的折叠能力依赖于伴侣蛋白的丰度，伴侣蛋白的丰度在响应UPR信号时增加，并依赖于足够的ATP供应来维持其活性。UPR的一个重要分支需要XBP1 mRNA的剪接来形成XBP1转录因子。研究表明，在脂肪细胞分化过程中，成熟脂肪细胞分泌脂联素，以及B细胞向分泌抗体的浆细胞分化过程中，XBP1都是必需的。在这里，我们发现腺苷酸激酶2 (AK2)，一种在膜间空间调节腺嘌呤核苷酸相互转化的线粒体酶，在脂肪细胞和B细胞分化过程中被显著诱导。通过RNAi耗尽AK2会损害3T3-L1脂肪细胞的脂联素分泌，BCL1细胞的IgM分泌，并在两种细胞类型的分化过程中诱导UPR。这些结果揭示了线粒体支持内质网功能的新机制，并表明特定的线粒体缺陷可能导致UPR信号通路受损。UPR诱导需要AK2，这可以解释网状发育不良的严重造血缺陷的发病机制，这是一种与人类AK2基因突变相关的疾病。
The unfolded protein response (UPR) is a homeostatic signaling mechanism that balances the protein folding capacity of the endoplasmic reticulum (ER) with the secretory protein load of the cell. ER protein folding capacity is dependent on the abundance of chaperones, which is increased in response to UPR signaling, and on a sufficient ATP supply for their activity. An essential branch of the UPR entails the splicing of XBP1 mRNA to form the XBP1 transcription factor. XBP1 has been shown to be required during adipocyte differentiation, enabling mature adipocytes to secrete adiponectin, and during differentiation of B cells into antibody-secreting plasma cells. Here we find that adenylate kinase 2 (AK2), a mitochondrial enzyme that regulates adenine nucleotide interconversion within the intermembrane space, is markedly induced during adipocyte and B cell differentiation. Depletion of AK2 by RNAi impairs adiponectin secretion in 3T3-L1 adipocytes, IgM secretion in BCL1 cells, and the induction of the UPR during differentiation of both cell types. These results reveal a new mechanism by which mitochondria support ER function and suggest that specific mitochondrial defects may give rise to impaired UPR signaling. The requirement for AK2 for UPR induction may explain the pathogenesis of the profound hematopoietic defects of reticular dysgenesis, a disease associated with mutations of the AK2 gene in humans.