FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Type I interferon (IFN) signaling induces interferon-stimulated genes (ISGs) crucial for antiviral defense but can cause inflammation and autoimmunity if dysregulated.
• The mRNA modification N6-methyladenosine (m6A) and its writers (METTL3/14) promote the type I IFN response.
• The role of the RNA demethylase fat mass and obesity-associated protein (FTO) in the type I IFN response was investigated.

Purpose of the Study:

• To determine the function of FTO in the type I IFN response.
• To elucidate the mechanism by which FTO regulates ISG expression and inflammation.

Main Methods:

• Investigated FTO's role in type I IFN response using depletion studies.
• Assessed FTO's catalytic activity in regulating ISG transcription.
• Examined the effect of FTO depletion on STAT3 activation and ISG expression.
• Utilized STAT3 depletion to confirm its role in FTO-regulated ISG induction.

Main Results:

• FTO suppresses the transcription of specific ISGs, including pro-inflammatory genes, requiring its catalytic activity but not via m6Am.
• FTO depletion activates STAT3, leading to increased expression of a subset of ISGs.
• STAT3 is partially required for the enhanced ISG induction observed upon FTO depletion.

Conclusions:

• FTO negatively regulates STAT3-mediated signaling that induces pro-inflammatory ISGs during the IFN response.
• FTO plays a significant role in suppressing inflammatory gene expression within the context of the type I IFN pathway.