Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial homeostasis is crucial for cellular function.
• GRSF1 (G-rich RNA sequence-binding factor 1) is an RNA-binding protein essential for maintaining mitochondrial integrity.
• Loss of GRSF1 leads to mitochondrial dysfunction, oxidative stress, and cellular senescence.

Purpose of the Study:

• To investigate the molecular pathways linking mitochondrial dysfunction caused by GRSF1 depletion to interleukin 6 (IL6) production.
• To elucidate the role of GRSF1 in regulating inflammatory responses.

Main Methods:

• Analysis of protein expression programs in GRSF1-depleted cells.
• Assessment of mitochondrial respiration and reactive oxygen species (ROS) levels.
• Investigation of DNA damage, mTOR signaling, and NF-κB activation.
• Quantification of IL6 gene transcription and secretion.

Main Results:

• GRSF1 depletion impaired mitochondrial respiratory complexes I and IV, increasing ROS and DNA damage.
• Oxidative stress activated the mTOR pathway, which subsequently activated NF-κB.
• Activated NF-κB induced IL6 gene transcription, driving a pro-inflammatory response.
• GRSF1 deficiency led to a senescent phenotype with elevated IL6 secretion.

Conclusions:

• GRSF1 is critical for maintaining mitochondrial homeostasis and preventing cellular senescence.
• GRSF1 loss triggers a pro-inflammatory cascade via oxidative stress, mTOR, and NF-κB activation.
• GRSF1 acts as a key suppressor of IL6 production and associated inflammatory programs.