Title: Lymphotoxin alpha induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor
Authors: Etemadi, N
Holien, JK
Chau, D
Dewson, G
Murphy, JM
Alexander, WS
Parker, MW
Silke, J
Nachbur, U
Issue Year: 2013
Series FEBS JOURNAL: 280(21): 5283-5297
Abstract Both of the TNF superfamily ligands, TNF and LT alpha, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LT alpha but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LT beta to activate LT beta R, which is consistent with the similar phenotypes of the LT alpha and LT beta R deficient mice. However, it has also been reported that the LT alpha(3) homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LT alpha(3)/TNFR1 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 alpha 3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LT alpha(3). Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LT alpha(3). Our results imply that the reasons for the conservation of LT alpha are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LT alpha to form heterotrimers with LT beta.
URI: https://publications.svi.edu.au/publications/1724
Other Identifiers 10.1111/febs.12419
Publication type Article
Grant ID GNT1021645
Find it online http://onlinelibrary.wiley.com/store/10.1111/febs.12419/asset/febs12419.pdf;jsessionid=B2727F95D21625CDC5B64B7CFA75EFA3.f03t04?v