The Role of Stat1 in Mitochondria

描述(由申请人提供)：众所周知，Stat转录因子家族控制核编码细胞基因的表达。作为细胞与各种细胞因子和生长因子孵育的结果，STAT被酪氨酸磷酸化激活，导致它们的核转位。以前的研究已经报道，由于细胞与1型干扰素(干扰素α/β)孵育，几个线粒体编码的RNA的表达受到抑制。本申请提供的初步数据表明，STAT1在人类和小鼠细胞的线粒体中都存在。在原代小鼠PRO B细胞和从STAT1缺失小鼠分离的MEF中，编码线粒体合成蛋白的所有RNA的表达都比来自野生型窝产仔的PRO B细胞或MEF高3到8倍。此外，我们能够证明STAT1结合到线粒体基因组的D-环区，在那里线粒体编码基因的转录被启动。我们假设STAT1在线粒体编码的mRNAs的表达中发挥重要作用，并可能参与电子传递的其他功能。为了验证这一假说，我们将执行以下特定目的：1)确定线粒体编码RNA的表达减少是否由定位于线粒体的STAT1介导，并确定其在线粒体中定位所需的STAT1结构域。2)确定细胞的病毒感染或干扰素β处理是否改变线粒体编码的mRNAs的表达和线粒体呼吸。

DESCRIPTION (provided by applicant): The Stat family of transcription factors are well known to control the expression of nuclear encoded cellular genes. As a consequence of incubation of cells with a variety of cytokines and growth factors the Stats are activated by tyrosine phosphorylation resulting in their nuclear translocation. Previous studies have reported that the expression of several mitochondria encoded RNAs is inhibited as a result of incubation of cells with type one interferons (IFN alpha/beta). Preliminary data presented in this application indicates that Stat1 is constitutively present in the mitochondria of both human and mouse cells. In primary murine pro B cells and MEFs isolated from Stat1-null mice the expression of all RNAs that encode mitochondria synthesized proteins are elevated 3 to 8 fold compared to pro B cells or MEFs derived from wild type littermates. Furthermore, we are able to demonstrate that Stat1 binds to the D-loop region of the mitochondrial genome where transcription of the mitochondrially encoded genes is initiated. We hypothesize that Stat1 plays an important role in the expression of mitochondrial encoded mRNAs and possibly other functions involved in electron transport. To test this hypothesis we will perform the following specific aims: 1) Determine whether decreased expression of mitochondria-encoded RNAs is mediated by Stat1 localized in the mitochondria and identify the domains in Stat1 required for its localization in the mitochondria. 2) Determine whether viral infection or IFN beta treatment of cells alters expression of mitochondria-encoded mRNAs and mitochondria respiration.