Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program.
Nucleic Acids Res
; 47(5): 2472-2486, 2019 03 18.
Article
in En
| MEDLINE
| ID: mdl-30753671
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukin-6
/
Poly(A)-Binding Proteins
/
TOR Serine-Threonine Kinases
/
Inflammation
Limits:
Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2019
Document type:
Article
Affiliation country:
Estados Unidos