Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis

Abstract

Pyroptosis, apoptosis, necroptosis, and ferroptosis, which are the most well-studied regulated cell death (RCD) pathways, contribute to the clearance of infected or potentially neoplastic cells, highlighting their importance in homeostasis, host defense against pathogens, cancer, and a wide range of other pathologies. Although these four RCD pathways employ distinct molecular and cellular processes, emerging genetic and biochemical studies have suggested remarkable flexibility and crosstalk among them. The crosstalk among pyroptosis, apoptosis and necroptosis pathways is more evident in cellular responses to infection, which has led to the conceptualization of PANoptosis. In this review, we provide a brief overview of the molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis and their importance in maintaining homeostasis. We discuss the intricate crosstalk among these RCD pathways and the current evidence supporting PANoptosis, focusing on infectious diseases and cancer. Understanding the fundamental processes of various cell death pathways is crucial to inform the development of new therapeutics against many diseases, including infection, sterile inflammation, and cancer.

Fig. 1. Molecular mechanisms of extrinsic and intrinsic apoptosis.

Extrinsic apoptosis: Binding of a ligand such as FASL, TNF, TRAIL, and TWEAK to one of several death receptors (TNF receptor superfamily) initiates extrinsic apoptosis by triggering receptor oligomerization and the recruitment of adaptor proteins containing death domains such as TRADD and FADD. The resulting complexes activate caspase-8, which activates executioners caspase-3 and caspase-7. Intrinsic apoptosis: Diverse cytotoxic stimuli, such as DNA damaging agents and stress, activate BH3-only family members, thereby activating pro-apoptotic effectors BAX and BAK, which then disrupt the mitochondrial outer membrane. The cytochrome c released from the mitochondria interacts with APAF1 to form apoptosomes, which in turn activate the initiator caspase-9. Crosstalk between the extrinsic and intrinsic pathways can occur through BID cleavage by caspase-8, leading to activation of BAX and BAK. The two pathways converge at activation of the effector caspases (caspase-3 and caspase-7).

Fig. 2. Inflammasome activation and pyroptosis.

Certain pathogens, PAMPs, and DAMPs are sensed by specific sensors to assemble an inflammasome consisting of a sensor, ASC, and caspase-1. Active caspase-1 cleaves pro-IL-18 and pro-IL-1β into their mature forms. Active caspase-1, caspase-11, and caspase-8 cleave GSDMD to free the N-terminal region, which undergoes oligomerization to form pores in the plasma membrane. Active caspase-8 also cleaves GSDME and GSDMC. Pore formation in the plasma membrane by GSDMs causes cell lysis and release of intracellular contents and the inflammatory cytokines IL-18 and IL-1β following their maturation by caspase-1.

Fig. 3. Molecular mechanisms of necroptosis.

TNF ligation or LPS stimulation results in activation of NF-κB signaling. Inactivation of NF-κB signaling or engagement of death receptors triggers the assembly of an apoptosis-inducing complex consisting of FADD, caspase-8, and RIPK1. When caspase-8 is inhibited, RIPK1 and RIPK3 form necrosomes through homotypic interactions with RHIM, resulting in phosphorylation of MLKL. Phosphorylated MLKL undergoes oligomerization and induces membrane rupture.

Fig. 4. Molecular mechanisms of ferroptosis.

Ferroptosis is primarily driven by iron-dependent lipid peroxidation. Iron bound to transferrin is transported into cells by TFRC1. NCOA4-mediated ferritinophagy increases the free iron pool. Ferroptosis is inhibited by GSH, the synthesis of which involves the uptake of cystine via the cystine-glutamate antiporter (system X_c^-). Using GSH as a cofactor, GPX4 reduces phospholipid hydroperoxides to their corresponding alcohols. The FSP1-CoQ10 system inhibits ferroptosis.

Fig. 5. Triggers and molecules involved in PANoptosome assembly.

Pathogens such as IAV, HSV1, Francisella, and Yersinia and other agents such as IFN + KPT and TNF + IFNγ have been identified to induce PANoptosis. ZBP1 senses IAV or endogenous Z-NA to assemble ZBP1 PANoptosomes consisting of ZBP1 and other cell death molecules. CASP6 potentiates the interaction between RIPK3 and ZBP1. AIM2 senses dsDNA during HSV1 or Francisella infection to assemble the AIM2 PANoptosome. TNF + IFNγ activates STAT1 to induce IRF1-dependent NO release, which activates CASP8 and RIPK3 to trigger PANoptosis. During Yersinia infection, RIPK1 assembles the RIPK1 PANoptosome.