The double-edged functions of necroptosis

Abstract

Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a "double-edged sword" in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death.

Fig. 1. Several switch events exist in necroptosis.

In TNFR1-induced necroptosis, cells undergo necroptosis only when RIPK1 is deubiquitinated, and caspase-8 is inhibited or absent. All death receptor-induced necroptosis requires the interaction of molecules containing the RHIM domain with the RHIM domain of RIPK3 to activate necroptosis.

Fig. 2. The molecular mechanisms of necroptosis.

Tumor necrosis factor alpha (TNF-α) binds to TNF receptors, leading to the assembly of complex I, which is mainly composed of TRADD, RIPK1, CIAP1/2, and TRAF2/5. The ubiquitination status of RIPK1 determines the fate of complex I. In most cases, complex I recruits the TAK and IKK complexes, leading to the activation of the NF-κB pathway, which promotes inflammatory factor production and cell survival. When CYLD deubiquitinates RIPK1, A20, USP21, or USP20, both TRADD and RIPK1 detach from complex I and assemble into complex IIa with FADD and caspase-8, leading to apoptosis. RIPK1 can also form complex IIb with FADD and caspase-8. ANKRD13a restricts the interaction of FADD and caspase-8 with ubiquitinated-RIPK1 by binding to the latter via its Ub-interacting motif. When caspase-8 is inhibited or absent, RIPK1 binds to RIPK3 via the RHIM domain, leading to RIPK3 phosphorylation and necrosome formation. An increase in cytoplasmic pH mediated by the activity of the Na⁺/H⁺ exchanger SLC9A1 and osmotic stress promotes necroptosis by directly stimulating the kinase activity of RIPK3. Heat stress activates ZBP1 through the transcription factor HSF1, which binds to and phosphorylates RIPK3, leading to the induction of pyroptosis through the MLKL pathway. Subsequently, MLKL is phosphorylated and oligomerized, translocates to the cell membrane, and promotes membrane rupture. Multiple death receptors can mediate the occurrence of necroptosis (see Table 1). NINJ1 is only partially involved in the release of Lactate Dehydrogenase (LDH, a standard measure of PMR) during MLKL-dependent necroptosis. In addition, ESCRT-III can repair plasma membrane rupture downstream of MLKL.

Fig. 3. The “Tai Chi” model of necroptosis in regulating life and death.

The adverse effects caused by necroptosis can be turned into positive effects; similarly, an excess of positive effects can lead to death in the host cells. Therefore, controlling the balance between life and death represents a considerable challenge.