MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• Metastatic tumor antigen 1 (MTA1) is a chromatin modifier, and transglutaminase 2 (TG2) is a multifunctional enzyme, both activated during inflammation.
• The coordinated regulation of inflammatory responses by MTA1 and TG2 is not well understood.

Purpose of the Study:

• To investigate the role of MTA1 in regulating TG2 expression in mammalian cells stimulated with bacterial lipopolysaccharide (LPS).
• To elucidate the molecular mechanisms underlying MTA1-mediated regulation of TG2 expression during inflammatory signaling.

Main Methods:

• Investigated MTA1's impact on global gene expression in LPS-stimulated cells.
• Analyzed TG2 expression levels in cells with varying MTA1 status.
• Examined the recruitment of MTA1, p65RelA, and RNA polymerase II to the TG2 promoter using chromatin immunoprecipitation assays.
• Utilized NF-κB pathway inhibitors to assess their effect on TG2 expression and p65 recruitment.

Main Results:

• MTA1 depletion significantly impaired both basal and LPS-induced TG2 expression.
• TG2 was identified as a chromatin target regulated by MTA1 and NF-κB signaling in LPS-stimulated cells.
• LPS stimulation enhanced the recruitment of MTA1, p65RelA, and RNA polymerase II to the TG2 promoter's NF-κB sites.
• NF-κB pathway inhibition blocked p65 recruitment and TG2 expression.

Conclusions:

• MTA1 plays an obligatory coregulatory role in TG2 expression.
• The MTA1-TG2 pathway is involved in LPS modulation of NF-κB signaling in macrophages.
• These findings highlight a novel mechanism of inflammatory gene regulation involving MTA1 and TG2.