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Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor
Author(s) -
Etemadi Nima,
Holien Jessica K.,
Chau Diep,
Dewson Grant,
Murphy James M.,
Alexander Warren S.,
Parker Michael W.,
Silke John,
Nachbur Ueli
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12419
Subject(s) - necroptosis , tumor necrosis factor alpha , lymphotoxin , traf2 , mediator , microbiology and biotechnology , apoptosis , tumor necrosis factor receptor 1 , signal transduction , ripk1 , biology , immunology , programmed cell death , genetics , tumor necrosis factor receptor
Both of the TNF superfamily ligands, TNF and LT α, can bind and signal through TNFR 1 and TNFR 2, yet mice mutant for each have different phenotypes. Part of this difference is because LT α but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LT β to activate LT βR, which is consistent with the similar phenotypes of the LT α and LT βR deficient mice. However, it has also been reported that the LTα 3 homotrimer signals differently than TNF through TNFR 1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF / TNFR 1 interface compared to the LT α 3 / TNFR 1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LT α 3 to induce TNFR 1‐dependent apoptosis or necroptosis, and if there were different requirements for c IAP s and Sharpin to transmit the TNFR 1 signal, we compared the ability of cells to respond to TNF and LT α 3 . Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR 1 in response to TNF and LT α 3 . Our results imply that the reasons for the conservation of LT α are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LT α to form heterotrimers with LT β. Structured digital abstractLT alpha physically interacts with RIPK1 and cIAP1 by tandem affinity purification ( View interaction ) TNF and TNF bind by blue native page ( View interaction ) LT alpha and LT alpha bind by blue native page ( View interaction ) TNF physically interacts with cIAP1 and RIPK1 by tandem affinity purification ( View interaction )