Severe Impairment of TNF Post-transcriptional Regulation Leads to Embryonic Death

Elise Clayer; Destiny Dalseno; Andrew Kueh; Derek Lacey; Minhsuang Tsai; Elyas H Arvell; Verena C Wimmer; Philippe Bouillet

doi:10.1016/j.isci.2020.101726

Severe Impairment of TNF Post-transcriptional Regulation Leads to Embryonic Death

iScience. 2020 Oct 23;23(11):101726. doi: 10.1016/j.isci.2020.101726. eCollection 2020 Nov 20.

Authors

Elise Clayer^{1

2}, Destiny Dalseno^{1

2}, Andrew Kueh^{1

2}, Derek Lacey^{1

2}, Minhsuang Tsai^{1

2}, Elyas H Arvell^{2

3}, Verena C Wimmer^{1

2}, Philippe Bouillet^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
² Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3052, Australia.
³ The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.

Abstract

Post-transcriptional regulation mechanisms control mRNA stability or translational efficiency via ribosomes, and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. Transcriptional regulation of Tnf has been well studied and found to be important for the rapid induction of Tnf mRNA and regulation of the acute phase of inflammation, whereas study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, to that of the constitutive decay element (CDE). We have identified another regulatory element (NRE) in the 3' UTR of Tnf and demonstrate that ARE, CDE, and NRE cooperate in vivo to efficiently downregulate Tnf expression and prevent autoimmune inflammatory diseases. We also show that excessive TNF may lead to embryonic death.

Keywords: Developmental Biology; Immunology; Molecular Biology.