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. 2020 Jul 13;10(10):1880–1903. doi: 10.1016/j.apsb.2020.07.003

Table 1.

Key lysosomal factors that are involved in regulated necrosis.

Type of regulated necrosis Key lysosomal factor

  • Necroptosis
  • 1.
    Lysosomal membrane permeabilization (LMP) with subsequent cathepsins release:
    • (1)
      Increased intracellular Ca2+ concentration activated Ca2+-dependent enzymes, including calpains and phospholipase, causing LMP26, 27, 28.
    • (2)
      Enhanced ROS generation may also induce LMP under certain circumstances29, 30, 31, 32.
    • (3)
      Cathepsins (mainly B and D) released from lysosome as a result of LMP display hydrolytic functions. They interact with cytosolic signaling proteins, gradually self-digest certain cellular constituents, enhance LMP, induce mitochondrial and plasma membrane permeabilization, and finally cause cell death26,27,33, 34, 35, 36, 37, 38, 39.
  • 2.
    Lysosomal regulation of RIPK1 and RIPK3:
    • Lysosome maintains the normal homeostasis of RIPK1 and RIPK3 through their post-translational modification in TNF-induced necroptosis. Ubiquitylated RIPKs co-localize to lysosome with carboxyl-terminus of HSP70-interacting protein (CHIP) and get degraded in a lysosome-dependent pathway40,41.
  • 3.
    Others:
    • Lysosomal integrity takes part in the membrane repair system of plasma membrane during necroptosis, which consists of lysosomal degradation of endocytic MLKL and the exocytosis of MLKL on plasma membrane42.

  • Ferroptosis
  • 1.
    Lysosome can regulate iron homeostasis:
    • (1)
      Lysosome has the highest abundance of active catalytic Fe2+ among all the organelles43. It can liberate active iron from ferritin (the main storage form of iron) in an autophagic process called ferritinophagy with the help of the cargo receptor nuclear receptor coactivator 4 (NCOA4). Autophagic degradation of ferritin is mediated by lysosomal acid hydrolases like cathepsin B inside lysosome. Increased free iron levels enhance lipid peroxides and ROS generation, which are prerequisite for ferroptosis44, 45, 46, 47, 48, 49.
    • (2)
      Lysosome stores iron imported by endocytosis of transferrin. Lysosome disrupters siramesine along with lapatinib increase transferrin expression and attenuate ferriportin-1 expression50, 51, 52.
  • 2.
    Chaperon-mediated autophagy (CMA):
    • Lysosome mediates the degradation of GPX4 in a manner of CMA, with an increased level of LAMP-2A53,54.
  • 3.
    Clockophagy:
    • Lysosome affects ferroptosis by selective autophagic degradation of core circadian clock protein ARNTL, named clockophagy which facilitates the expression of egl nine homolog 2 (EGLN2), thus destabilizing HIF1A and ultimately promoting LPO and subsequent ferroptosis55,56.

  • Pyroptosis
  • 1.
    Lysosome promotes NLRP3 inflammasome activation:
    • (1)
      Lysosomal disrupters like crystalline materials, chemical compounds, nanomaterials, and rare earth oxide cause lysosomal rupture23,39,57, 58, 59.
    • (2)
      Cathepsin B release as a result of lysosomal disruption attributes to NLRP3 activation. It binds to and activates NLRP3. Other cathepsins including cathepsins D, L, and X may also stimulate pyroptosis59, 60, 61, 62, 63, 64, 65.
    • (3)
      ROS production and K+ efflux as downstream events of lysosomal rupture contribute to the activation of inflammasome as well66, 67, 68.
  • 2.

    Lysosomal permeabilization caused by HMGB1 avoided the lysosomal degradation of LPS, allowing LPS to stimulate pyroptosis by activating non-canonical inflammasome in endotoxemia69,70.

  • 3.

    In pyroptosis induced by the endocytosis of HMGB1, lysosome destabilization and cathepsin B release are necessary for pyroptosome formation71, 72, 73.

  • 4.

    The activation of NLRP3 inflammasome, non-canonical inflammasome, or pyroptosome further activates corresponding caspase and GSDMD, leading to final cell death.
Parthanatos The occurrence of parthanatos may be accompanied by the activation of calpains, LMP, and cathepsin B/D release74,75.
NETosis NETs contains lysosomal enzymes. And instability of lysosome can cause the immediate formation of NETs and promote NETosis18,76,77.
Cyclophilin D-mediated necrosis Mitochondrial ROS induced generation of lysosomal ceramide activates cytosolic protein BAX which triggers a cascade of reaction with ultimate necrosis78.