Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway.
TNF-like weak inducer of apoptosis, TWEAK, is a typical member of the TNF ligand family. Thus, it is initially expressed as a type II transmembrane protein from which a soluble variant can be released by proteolytic processing. In this study, we show that membrane TWEAK is superior to soluble variant of TWEAK (sTWEAK) with respect to the activation of the classical NF-kappaB pathway, whereas both TWEAK variants are potent inducers of TNFR-associated factor-2 depletion, NF-kappaB-inducing kinase accumulation and p100 processing, hallmarks of activation of the noncanonical NF-kappaB pathway. Like other soluble TNF ligands with a poor capability to activate their corresponding receptor, sTWEAK acquires an activity resembling those of the transmembrane ligand by oligomerization or cell surface-immobilization. Blockade of the Fn14 receptor inhibited NF-kappaB signaling irrespective of the TWEAK form used for stimulation, indicating that the differential activities of the two TWEAK variants on classical and noncanonical NF-kappaB signaling is not related to the use of different receptors.
Roos
Claudia
C
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
Wicovsky
Andreas
A
Müller
Nicole
N
Salzmann
Steffen
S
Rosenthal
Tina
T
Kalthoff
Holger
H
Trauzold
Anna
A
Seher
Axel
A
Henkler
Frank
F
Kneitz
Christian
C
Wajant
Harald
H
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D012995:Solubility; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074050:TWEAK Receptor; D000097782:NF-kappaB-Inducing Kinase
D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D000074050:TWEAK Receptor; D000097782:NF-kappaB-Inducing Kinase; C000613297:TNFRSF12A protein, human; C000613299:Tnfrsf12a protein, mouse