An outline of necrosome triggers.

Tom Vanden Berghe,Peter Vandenabeele,Behrouz Hassannia

doi:10.1007/s00018-016-2189-y

Abstract

Necroptosis was initially identified as a backup cell death program when apoptosis is blocked. However, it is now recognized as a cellular defense mechanism against infections and is presumed to be a detrimental factor in several pathologies driven by cell death. Necroptosis is a prototypic form of regulated necrosis that depends on activation of the necrosome, which is a protein complex in which receptor interacting protein kinase (RIPK) 3 is activated. The RIP homotypic interaction motif (RHIM) is the core domain that regulates activation of the necrosome. To date, three RHIM-containing proteins have been reported to activate the kinase activity of RIPK3 within the necrosome: RIPK1, Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), and DNA-dependent activator of interferon regulatory factors (DAI). Here, we review and discuss commonalities and differences of the increasing number of activators of the necrosome. Since the discovery that activation of mixed lineage kinase domain-like (MLKL) by RIPK3 kinase activity is crucial in necroptosis, interest has increased in monitoring and therapeutically targeting their activation. The availability of new phospho-specific antibodies, pharmacologic inhibitors, and transgenic models will allow us to further document the role of necroptosis in degenerative, inflammatory and infectious diseases.

Highlights

Rudolf Virchow (1821–1902, Prussia), founder of the cell theory (Omnis cellula e cellula) and cellular pathology, referred to tissue injury as ‘‘parenchymatous inflammation’’ and introduced the idea that tissue injury is caused by pathological changes within the cells
Since the discovery that activation of mixed lineage kinase domain-like (MLKL) by RIPK3 kinase activity is crucial in necroptosis, interest has increased in monitoring and therapeutically targeting their activation
We provide a snapshot of the activation of RIPK3 within the necrosome, typically by the three RIP homotypic interaction motif (RHIM)-containing proteins RIPK1, Toll/IL-1 receptor domain-containing adaptor inducing IFN-b (TRIF) and DNA-dependent activator of interferon regulatory factors (DAI)

Summary

Introduction

Rudolf Virchow (1821–1902, Prussia), founder of the cell theory (Omnis cellula e cellula) and cellular pathology, referred to tissue injury as ‘‘parenchymatous inflammation’’ and introduced the idea that tissue injury is caused by pathological changes within the cells. Necroptosis, the best-characterized form of regulated necrosis, is mediated by the concerted action of receptor interacting protein kinase (RIPK) 3 and mixed lineage kinase domain-like (MLKL). We provide a snapshot of the activation of RIPK3 within the necrosome, typically by the three RHIM-containing proteins RIPK1, Toll/IL-1 receptor domain-containing adaptor inducing IFN-b (TRIF) and DNA-dependent activator of interferon regulatory factors (DAI).

Results

Conclusion