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Updated: Jan 21, 2026
16:07
Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody mAb by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
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Palmitoylation is required for TNF-R1 signaling
Philipp Zingler1, Vinzenz Särchen1, Timo Glatter2
1Institute of Immunology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Cell Communication and Signaling : CCS
|August 7, 2019
Summary
Dynamic palmitoylation of TNF-R1 controls cell fate. This modification regulates TNF-R1 localization, influencing cell survival or death signaling pathways.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Tumor necrosis factor (TNF) binding to TNF-receptor 1 (TNF-R1) dictates cell survival or death.
- TNF-R1's subcellular location determines its signaling outcome: plasma membrane retention promotes survival, while endocytosis triggers cell death.
- The mechanism for recruiting TNF-R1 signaling complexes to specific subcellular locations remains unclear.
Purpose of the Study:
- To investigate the role of protein palmitoylation in regulating TNF-R1 signaling.
- To elucidate how palmitoylation influences TNF-R1's subcellular localization and subsequent signal transduction.
- To identify key molecular players involved in TNF-R1 palmitoylation and depalmitoylation.
Main Methods:
- Utilized acyl resin assisted capture (AcylRAC) to enrich palmitoylated proteins from human monocytic U937 cells.
- Performed western blot and mass spectrometry to identify palmitoylated proteins, including TNF-R1.
- Validated TNF-R1 palmitoylation via metabolic labeling and analyzed the involvement of palmitoyl thioesterase 2 (APT2) using enzyme assays, pharmacological inhibition, and shRNA.
- Investigated the functional impact of TNF-R1 palmitoylation site mutations on cellular readouts like apoptosis, NF-κB activation, and TNF-R1 internalization.
Main Results:
- Identified dynamic S-palmitoylation as a novel mechanism controlling selective TNF signaling.
- Demonstrated that TNF-R1 is constitutively palmitoylated and undergoes depalmitoylation upon ligand (TNF) binding.
- Showed that APT2 is involved in TNF-R1 depalmitoylation and subsequent TNF-induced NF-κB activation.
- Found that mutation of the palmitoylation site C248 disrupts TNF-R1 plasma membrane localization and proper signal transduction.
Conclusions:
- Palmitoylation represents a new regulatory layer in TNF-R1 signaling, acting at an early step of the cascade.
- Dynamic regulation of TNF-R1 palmitoylation controls its subcellular localization and downstream signaling outcomes.
- Understanding this mechanism may lead to novel therapeutic strategies for diseases involving TNF signaling.
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