Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program. Issue 5 (11th February 2019)

• Record Type: Journal Article
• Authors: Noh, Ji Heon; Kim, Kyoung Mi; Pandey, Poonam R; Noren Hooten, Nicole; Munk, Rachel; Kundu, Gautam; De, Supriyo; Martindale, Jennifer L; Yang, Xiaoling; Evans, Michele K; Abdelmohsen, Kotb; Gorospe, Myriam
• Is Part Of: Nucleic acids research. Volume 47:Issue 5(2019)
• Page Start: 2472
• Page End: 2486
• Publication Date: 2019-02-11
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkz082
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: The RNA-binding protein GRSF1 (G-rich RNA sequence-binding factor 1) critically maintains mitochondrial homeostasis. Accordingly, loss of GRSF1 impaired mitochondrial respiration and increased the levels of reactive oxygen species (ROS), triggering DNA damage, growth suppression, and a senescent phenotype characterized by elevated production and secretion of interleukin (IL)6. Here, we characterize the pathways that govern IL6 production in response to mitochondrial dysfunction in GRSF1-depleted cells. We report that loss of GRSF1 broadly altered protein expression programs, impairing the function of respiratory complexes I and IV. The rise in oxidative stress led to increased DNA damage and activation of mTOR, which in turn activated NF-κB to induce IL6 gene transcription and orchestrate a pro-inflammatory program. Collectively, our results indicate that GRSF1 helps preserve mitochondrial homeostasis, in turn preventing oxidative DNA damage and the activation of mTOR and NF-κB, and suppressing a transcriptional pro-inflammatory program leading to increased IL6 production.