The molecular machinery of regulated cell death

Abstract

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

Fig. 1

Timeline of the terms used in cell death research

Fig. 2

Extrinsic and intrinsic apoptosis. Extrinsic apoptosis is induced by the addition of death receptor ligands or by the withdrawal of dependence receptor ligands. CASP8 and CASP10 initiate death receptor-mediated extrinsic apoptosis, whereas CASP9 initiates the withdrawal of dependence receptor ligand-mediated extrinsic apoptosis. Pro-CASP8 and pro-CASP10 are enzymatically inactive until they interact with FADD (Fas-associated via death domain), which is activated upon binding to cell death receptors responding to their ligands. DNA damage, hypoxia, metabolic stress, and other factors can induce intrinsic apoptosis, which begins with MOMP and leads to the release of mitochondrial proteins (e.g., CYCS) into the cytosol. Cytosolic CYCS interacts with APAF1, which recruits pro-CASP9 to form the apoptosome. MOMP is tightly controlled by the BCL2 family, including its pro-apoptotic and anti-apoptotic members. CASP3, CASP6, and CASP7 are considered the common effector caspases for both extrinsic and intrinsic apoptosis. In addition, the extrinsic pathway can trigger intrinsic mitochondrial apoptosis through the generation of truncated BID (tBID) by activated CASP8. tBID can further translocate to mitochondria and cause MOMP through the activation of BAX and BAK1

Fig. 3

Core molecular mechanism of non-apoptotic regulated cell death. a RIPK3-stimulated MLKL is necessary for membrane rupture formation in necroptosis. Upstream elicitors include DR, TLR, and viruses, which induce RIPK3 activation through RIPK1, TICAM1, and ZBP1, respectively. In addition, RIPK3 is activated by AR via an unknown adaptor protein or kinases. b Pyroptosis is mostly driven by GSDMD after cleavage of this protein by CASP1 and CASP11 in response to PAMPs and DAMPs, or cytosolic LPS. c Ferroptosis is a form of cell death that relies on the balance between iron accumulation-induced ROS production and the antioxidant system during lipid peroxidation. The ACSL4-LPCAT3-ALOX15 pathway mediates lipid peroxidation. In contrast, several antioxidant systems, especially system xc^- that includes the core components SLC7A11, GPX4, and NFE2L2, inhibit this process. d Parthanatos is a PARP1-dependent form of cell death that relies on the AIFM1-MIF pathway. e Entotic cell death is a form of cellular cannibalism through the activation of entosis followed by the engulfing and killing of cells through LAP and the lysosomal degradation pathway. RHOA, ROCK, myosin, and CDC42 are required for entosis. f Netotic cell death is driven by NET release, which is regulated by NADPH oxidase-mediated ROS production and histone citrullination. g Lysosome-dependent cell death is mediated by releasing hydrolytic enzymes (cathepsins) or iron upon LMP. h Autophagy-dependent cell death is driven by the molecular machinery of autophagy. i Alkaliptosis is driven by intracellular alkalinization after IKBKB-NF-κB pathway-dependent downregulation of CA9. j Oxeiptosis is an oxygen radical-induced form of cell death driven by the activation of the KEAP1-PGAM5-AIFM1 pathway

Fig. 4

Central role of TMEM173 in inflammation, immunity, and cell death. TMEM173 can be activated by cytosolic DNA sensors (e.g., CGAS, DDX41, MRE11, and IFI16), or cell surface receptors (e.g., ALK and EGFR) in response to various DNAs from the pathogen and host. The activation of STING not only promotes inflammation and the immune response through TBK1-mediated transcription factor activation, but also ignites various cell death pathways, including apoptosis, necroptosis, pyroptosis, and lysosome-dependent cell death