A novel role for Tm7sf2 gene in regulating TNFα expression

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• The Tm7sf2 gene encodes 3β-hydroxysterol Δ14-reductase, an endoplasmic reticulum protein.
• Its precise role in endoplasmic reticulum (ER) stress and inflammatory responses is not fully understood.

Purpose of the Study:

• To investigate the function of the Tm7sf2 gene in ER stress sensitivity and subsequent inflammation.
• To elucidate the relationship between Tm7sf2, the unfolded protein response (UPR), and inflammatory signaling pathways like NF-κB.

Main Methods:

• Utilized Tm7sf2(+/+) and Tm7sf2(-/-) mouse embryonic fibroblasts (MEFs) to study thapsigargin-induced NF-κB activation in vitro.
• Employed genetically modified mice in an in vivo model of ER stress and inflammation.
• Assessed NF-κB activation, TNFα expression, and oedematogenic responses.

Main Results:

• Tm7sf2 deficiency leads to increased NF-κB activation and TNFα up-regulation, indicating a role in an anti-inflammatory loop.
• Absence of Tm7sf2 inhibits liver X receptor (LXR) signaling.
• In vivo studies showed increased renal TNFα expression and oedema in Tm7sf2(-/-) mice upon ER stress induction.

Conclusions:

• The Tm7sf2 gene controls the unfolded protein response and acts as a key regulator of an anti-inflammatory loop.
• Tm7sf2 plays a crucial role in mitigating inflammatory responses during ER stress.
• This study reveals cross-talk between metabolic pathways (cholesterol biosynthesis) and inflammatory responses, mediated by the Tm7sf2 gene.