The role of lysosome in regulated necrosis

Abstract

Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules, particles, and organelles. Currently, the pivotal role of lysosome in regulating cell death is drawing great attention. Over the past decades, we largely focused on how lysosome influences apoptosis and autophagic cell death. However, extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis (RN). Different types of RN have been uncovered, among which, necroptosis, ferroptosis, and pyroptosis are under the most intensive investigation. It becomes a hot topic nowadays to target RN as a therapeutic intervention, since it is important in many patho/physiological settings and contributing to numerous diseases. It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases. Therefore, we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN, especially in that of necroptosis, ferroptosis, and pyroptosis.

Keywords: Ferroptosis; Lysosome; Necroptosis; Pyroptosis; Regulated necrosis.

Graphical abstract

Figure 1

Classification of cell death. Cell death can be divided into ACD and programmed cell death (PCD). PCD includes apoptosis, autophagic cell death, and RN. RN comprises necroptosis, ferroptosis, pyroptosis, parthanatos, oxytosis, NETosis, pyronecrosis, cyclophilin D-mediated necrosis, and MPT-driven necrosis, etc.

Figure 2

Lysosome and necroptosis. Necroptosis occurs in the context of caspase-8 inhibition (Z-VAD-fmk, FLIP, Casp8 knockout, or Fadd knockout). Activated receptors on the membrane attract and activate RIPK1, which consecutively recruits and phosphorylates RIPK3 and MLKL. Phosphorylated MLKL translocates to plasma membrane, ending up with Na⁺ or Ca²⁺ influx. ER stress, as a result of RIPK3 and MLKL phosphorylation, also causes Ca²⁺ dysregulation. Increased Ca²⁺ concentration activates Ca²⁺ dependent enzymes in cytosol, particularly calpains and cPLA2, which can later cause LMP. In addition, mitochondria- and NOX-dependent ROS production is another source of LMP inducer. The generation of ROS relies on necrosomal RIPK3 and it in turn facilitates RIPK1 autophosphorylation. Subsequently, disturbed lysosome releases acid hydrolases (especially cathepsins B and D) into cytoplasm, resulting in plasma membrane permeability and eventual necroptosis. Besides, lysosome is discovered to be essential for the post-translation of RIPK1 and RIPK3 which guarantees the occurrence of necroptosis. Cat: cathepsin; Casp: caspase.

Figure 3

Lysosome and ferroptosis. Ferroptosis occurs owing to the imbalance between ROS generation and antioxidant defense system. Iron promotes ROS accumulation by enhancing the enzymetic activity of LOX or through Fenton reaction. But GPX4, coming from increased Cys2, reduces oxidative injury. Lysosome affects ferroptosis via regulating iron homeostasis, CMA (lysosomal degradation of GPX4) or clockophagy (lysosomal degradation of circadian clock protein ARNTL, which facilitates EGLN2 expression, thus destabilizing HIF1A and promoting LPO with subsequent ferroptosis). Lysosome increases the concentration of intracellular active iron, and NCOA4-dependent ferritinophagy is the most important form. Ferritin is sequestered into autophagosomes and then delivered to lysosome for degradation, liberating iron from ferritin. Increased labile iron concentration mediated by ferritinophagy in turn engages the IRP–IRE iron homeostatic system which leads to a continuous increase of ferritin synthesis, thus forming a positive feedback. Moreover, lysosome may also be related to increased transferrin and attenuated ferroportin-1 expression. Cys2: cystine; TFR1: transferrin (TF) receptor 1.

Figure 4

Lysosome and pyroptosis. In pyroptosis, lysosomal rupture can be initiated by various crystalline materials, nano-particles, chemical compounds, rare earth oxide, and maybe ROS. Subsequent CatB release and K⁺ efflux activate NLRP3 inflammasome. But in pyroptosis induced by the endocytosis of HMGB1, lysosome destabilization and CatB release are necessary for pyroptosome formation. Activated NLRP3 inflammasome or pyroptosome stimulates caspase-1. CatB can be inhibited by Ca074Me, endogenous cystatin C, or genetic knockout of CatB. Lysosome destabilization caused by HMGB1 is also indispensable for LPS-induced activation of non-canonical inflammasome and caspase-11, since it allows LPS internalized through HMGB1–RAGE signaling pathway to escape from lysosomal degradation. Activated caspase-1 and -11 drive the cleavage of pro-IL-1β/18 and GSDMD, coordinating membrane lysis, mature IL-1β/18 release and ultimate pyroptosis. CatB: cathepsin B.