Many stimuli pull the necrotic trigger, an overview

Abstract

The lab of Jürg Tschopp was the first to report on the crucial role of receptor-interacting protein kinase 1 (RIPK1) in caspase-independent cell death. Because of this pioneer finding, regulated necrosis and in particular RIPK1/RIPK3 kinase-mediated necrosis, referred to as necroptosis, has become an intensively studied form of regulated cell death. Although necrosis was identified initially as a backup cell death program when apoptosis is blocked, it is now recognized as a cellular defense mechanism against viral infections and as being critically involved in ischemia-reperfusion damage. The observation that RIPK3 ablation rescues embryonic lethality in mice deficient in caspase-8 or Fas-associated-protein-via-a-death-domain demonstrates the crucial role of this apoptotic platform in the negative control of necroptosis during development. Here, we review and discuss commonalities and differences of the increasing list of inducers of regulated necrosis ranging from cytokines, pathogen-associated molecular patterns, to several forms of physicochemical cellular stress. Since the discovery of the crucial role of RIPK1 and RIPK3 in necroptosis, these kinases have become potential therapeutic targets. The availability of new pharmacological inhibitors and transgenic models will allow us to further document the important role of this form of cell death in degenerative, inflammatory and infectious diseases.

Figure 1

Breaks and gears on TNF-induced necroptosis. Upon TNF stimulation, TNFR1 complex I, important for cell survival and inflammatory signaling, is formed at the plasma membrane. Within this TNFR1 complex I, A20, an ubiquitin-editing enzyme, cIAP1, an ubiquitylating enzyme, LUBAC, a linear ubiquitylating enzyme complex, and TAK1^* negatively regulate TNF-induced necroptosis in L929sA cells. The transition from TNFR1 complex I to the cytosolic death-inducing TNFR1 complex II requires the activity of cylindromatosis (CYLD), a deubiquitylating enzyme. The composition of TNFR1 complex II determines the cell death outcome: apoptosis or necroptosis. Within TNFR1 complex II, the apoptotic machinery FADD, c-FLIP and caspase-8 suppresses the induction of necroptosis, which requires the kinase activity of RIPK1^* and RIPK3^*. ^*Refers to the implication of the kinase activity in the function indicated

Figure 2

Overview of different necrotic triggers and regulatory mechanisms. Necrosis can be elicited by a wide range of stimuli. (a) Necroptosis induced by DR (TNFR1, TRAIL-R or Fas) stimulation depends on the kinase activity of RIPK1^* and RIPK3^*. RIPK1 and RIPK3 are present with FADD, caspase-8, and possibly TRADD in TNFR1 complex II, which can induce apoptosis or necroptosis. The latter depends on the functional assembly of a RIPK1^*/RIPK3^* necrosome complex, which is inhibited by Nec-1. (b) TLR3 and TLR4 triggering induce necroptosis through RIPK1^* and RIPK3^*-mediated signaling (see text). (c) Physico-chemical stress-mediated necrotic cell death. Oxidative stress-, excitotoxin- or MNNG-induced necrosis require PARP1 activation. IAP depletion by etoposide or IAP antagonist treatment induces the spontaneous RIPK1-mediated assembly of the ripoptosome. (d) NLR stimulation can induce necrosis depending on the cellular context. Microbial infection of cells with S. flexneri, K. pneumoniae and N. gonorrheae triggers NLRP3/ASC-dependent necrosis in myeloid cells. In non-myeloid cells, S. flexneri-induced necrosis does not require NLRP3 or ASC and is negatively regulated by Nod1 and RIPK2. Whether the executioner mechanism of NLR-mediated necrosis is similar to necroptosis requires further research. (e) Upon initiation of necrosis, several factors become involved in the conditioning and execution of necrotic cell death. Important mediators are: the activities of cytosolic phospholipase A₂ (cPLA₂), lipoxygenase (LOX) and sphingomyelinase (SMase), which contribute to an increased reactive oxygen species (ROS) production and lipid peroxidation that damages cellular membranes, calcium-mediated calpain activation that results in lysosomal membrane permeabilization (LMP), activation of JUN N-terminal kinase (JNK) that triggers the degradation of ferritin thereby increasing the labile iron pool and consequently ROS generation and LMP, and alteration of the mitochondrial energy metabolism, which causes an enhanced ROS production and ATP depletion. zVAD-fmk^a: in certain cellular conditions, the induction of necrosis requires caspase inhibition (see text for more details)

Figure 3

Virus-induced necroptosis: VV infection enhances TNF-induced necroptosis, probably by endogenous TNF production. In contrast, infection with MCMV rescues cells from TNF-induced necroptosis through M45-mediated inhibition of RIPK1-RIPK3 interaction. Infection with a RHIM-mutated M45 or M45-deficient MCMV strain (MCMV^*) induces RIPK1-independent, RIPK3-dependent necroptosis. HSV-1 infection induces necroptosis, which can be blocked by Nec-1 treatment