Journal article

Lymphotoxin alpha induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

Nima Etemadi, Jessica K Holien, Diep Chau, Grant Dewson, James M Murphy, Warren S Alexander, Michael W Parker, John Silke, Ueli Nachbur



Both of the TNF superfamily ligands, TNF and LTα, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTα but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTβ to activate LTβR, which is consistent with the similar phenotypes of the LTα and LTβR deficient mice. However, it has also been reported that the LTα3 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 LTα3/TNFR1 structure revealed some differences that could affect signalling by the..

View full abstract


Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by Independent Research Institutes Infrastructure Support Scheme

Awarded by Australian Research Council

Awarded by NHMRC

Awarded by Swiss National Science Foundation (SNSF)

Funding Acknowledgements

We would like to thank P. Schneider for the initial LT alpha, TNF and TWEAK constructs that were adapted by us, and D. Vaux for comments on the manuscript. This work was supported by National Health and Medical Research Council of Australia (NHMRC) project grants 541901, 541902, 602516, 637342, and 1025594, program grant 1016647 and an Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the Australian National Health and Medical Research Council, the Australian Cancer Research Fund and Victorian State Government Operational Infrastructure Support. J. M. Murphy is supported by the Australian Research Council (Future fellowship FT100100100). W. S. Alexander is supported by the NHMRC (Research Fellowship 575501). M. W. Parker is an NHMRC Research Fellow. J. Silke is a member of the Scientific Advisory Board of TetraLogic Pharmaceuticals. U. Nachbur is supported by the Swiss National Science Foundation (SNSF, fellowship PA 00P3_126249).