Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Cell Metab. 2023 Aug 8;35(8):1441-1456.e9. doi: 10.1016/j.cmet.2023.06.019. Epub 2023 Jul 25.
This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.
本研究揭示了一种以前尚未描述的机制，即通过从非编码基因组区域转录的调节性 RNA 来限制肠道炎症。我们鉴定了 lncRNA HOXA11os 的一种新型转录本，其特异性表达于远端结肠，在结肠炎中降至无法检测的水平。HOXA11os 在基础条件下定位于线粒体，并与电子传递链 (ETC) 核心亚基相互作用以维持其活性。结肠髓样细胞中 HOXA11os 的缺乏导致复合物 I 缺乏、氧化磷酸化功能障碍 (OXPHOS) 和线粒体活性氧物质 (mtROS) 的产生。结果，HOXA11os 缺陷型小鼠自发发生肠道炎症，并且对结肠炎高度敏感。总的来说，这些研究确定了一个新的调节轴，其中长非编码 RNA 通过调节复合物 I 的活性来维持肠道内稳态并限制结肠炎症。
