The tumor necrosis factor receptor stalk regions define responsiveness to soluble versus membrane-bound ligand

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• Tumor necrosis factor receptors (TNFRs) and their ligands regulate immune responses.
• Differential responses to soluble TNF (sTNF) and membrane-bound TNF (mTNF) are observed among TNFR family members.
• The molecular mechanisms underlying this differential signaling remain unclear.

Purpose of the Study:

• To investigate the role of TNFR extracellular stalk regions in differential signaling responses to sTNF and mTNF.
• To identify the molecular determinants of TNFR signaling diversity.

Main Methods:

• Utilized a system of chimeric TNFRs (TNFR1 and TNFR2).
• Developed novel ligand variants to mimic membrane-bound TNF (mTNF) bioactivity.
• Assessed receptor enrichment, clustering, and preassembly in response to sTNF and mTNF.

Main Results:

• The membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are critical for controlling sTNF responsiveness.
• The TNFR2 stalk region inhibits receptor enrichment, clustering, and ligand-independent preassembly.
• This inhibition prevents sTNF-induced signaling but not mTNF-induced signaling.

Conclusions:

• TNFR stalk regions dictate differential signaling responses to soluble versus membrane-bound TNF.
• TNFR stalk regions offer potential therapeutic targets for modulating immune responses.
• Findings have implications for understanding other TNFR family member signaling.