The FAScinating truth: Innate immune signalling driven by caspase-8 cleavage of N4BP1.

Mutations in FAS play a crucial role in the development of severe immunodeficiency, which is promoted by aberrant T lymphocyte death. In addition to this, mutations in caspase-8 or FADD, its adaptor protein, mediate further downstream effects which render an individual higher susceptibility to viral and bacterial infections. Whilst caspase-8 or FADD has been shown to be implicated in promoting inflammatory responses, little is known with regards to the molecular mechanisms which underline immune deficiency and the substrates that capsase-8 targets. Elucidating these would shed important light on the process of innate immunity through the Toll-like receptors (TLRs) pathway.

In this impressive body of work, Gitlin et al. use IonOpticks Aurora Series columns to identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production. As such, N4BP1 deletion in mice increased the production of select cytokines upon stimulation of the Toll-like receptors TLR1/2, TLR7 or TLR9. Interestingly, the agonists of TLRs 3 or 4, that were not engaged by N4BP1, were shown to induce the capsase-8 dependent cleavage of N4BP1. This cleavage was also induced by Tumour necrosis factor (TNF) and enabled the effects of N4BP1 to be overridden, resulting in the production of inflammatory cytokines. Overall, this study pinpoints N4BP1 cleavage by caspase-8 as a key event during inflammation and provides an explanation as to why mutations of FADD and caspase-8 lead to severe immunodeficiency.

Read the full paper
Integration of innate immune signalling by caspase-8 cleavage of N4BP1.
Nature. 2020 Nov;587(7833):275-280. doi: https://www.nature.com/articles/s41586-020-2796-5. Epub 2020 Sep 24.
Gitlin AD, Heger K, Schubert AF, Reja R, Yan D, Pham VC, Suto E, Zhang J, Kwon YC, Freund EC, Kang J, Pham A, Caothien R, Bacarro N, Hinkle T, Xu M, McKenzie BS, Haley B, Lee WP, Lill JR, Roose-Girma M, Dohse M, Webster JD, Newton K, Dixit VM. 

Commentary by Andreia Almeida, PhD.

About the author
Andreia is an application scientist at IonOpticks playing a key role on the utilisation and development of next generation HPLC columns. Andreia has completed her PhD at Institute for Glycomics – Griffith University in Gold Coast with a strong focus on Glycomics & Glycoproteomics.