LBH is a neoplasm (tumor/cancer), he escapes death and has, for some reason, found a way to escape any forms of induced dead. (So he can't be killed by other cells nor the narrative.)

PIDW SJ is anoikis, he dies because there are no other cells around him that tell him to live. His conection with YQY is severed, and as its the main source of his signal to keep living, he comits apoptosis.

PIDW YQY is necrosis. he dies due to external damage, and his death isn't clean, infecting neighbouring tissue and causing more death in its wake. He would like to be apoptosis, he thinks he is apoptosis (a very organised way to die) but he is not. His death is messy and infects everything it touches.

PIDW NYY is apoptosis. She grows into a very good, meek woman, and in LBG's harem, she shrinks into herself and as she's obedient, if you tell her to, she would die in a very clean and orderly way, not causing many issues.

PIDW Haitang is also apoptosis. Her death wouldn't be loud, even if she would fight it more. She cannot bear the metabolites that have accumulated in her, she cannot bear the errors, and dies.

SVSS Haitang, though, is autophagy. Autophagy in cells is also associated with stress and neurodegenerative diseases. She realizes that there was osmething poisonous she didn't prevent, and she goes insane, her mind devouring herself and leading her towards death.

PIDW LQG is mitotic catastrophe. He notices that something went wrong, and if he doesnt die he will endanger others. Therefore he stops himself and kills himself. Just like cells noticing their mitosis is going wrong.

SJ in SVSS is autophagy - he dies, but his body is repurposed and reused by the body (the narrative), as everything he left enough got broken down and made into usable blocks with which to build new cells (SY's future.)

GYX - Fas Ligand induced death, he had to die for thr sake of the plot (the body narrative had to have him killed)

SXY is entosis. Another cell developed inside of her, and thus she the cell inside of her should have been killed by her organism (or OPM's poison). She sacrificed herself so that the internal cell could survive.

TLJ is pyroptosis, he is killed by inflammation (being attacked by righteous cultivators, then shackled). His new body is rejecting him, inflamation is making him disintegrate.

SY is parthanatos - his body accumulates qi (apoptosis inducing factors from the mitochondrium) and he dies due to overabundance of it. (Shizun explosion.)

The Devour Ring

In this act of microscopic cannibalism, known as entosis, one human cell engulfs another. A bit like a snake dislocating its jaw to eat a mouse (although 2000 times smaller) the predatory cell (on the left in these pictures) opens up its cytoplasm, forming a ring shape, pictured in 3D on the top row and in cross section beneath. Scientists find this ‘mechanical ring’ is riddled with a mechanical sensor called vinculin, and expands by coordinating stretchy actomyosin in the cells’ membranes at the adherens junction – the boundary where cells touch. The engulfed cell usually dies, so entosis is often considered a mysterious form of programmed cell death. Learning more about the ring, and how it forms, might offer clues into slowing cancer progression, where tumour cells sometimes use entosis to consume surrounding healthy tissue.

Written by John Ankers

Image from work by Manna Wang, Zubiao Niu and Hongquan Qin, and colleagues

Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China

Image originally published with a Creative Commons Attribution 4.0 International (CC BY 4.0)

Published in Cell Reports, August 2020

The regulation and stimulation of apoptosis. Apoptosis is driven by internal (intrinsic pathway) and external (extrinsic pathway) signals, and can also be induced by immune cells. Cells undergoing apoptosis tend to shrink, condense, and detach from surfaces including other cells. They develop blebs, fragment their nuclei and DNA (karyorrhexis), and recruit macrophages by displaying phosphatidylserine on their surface.

The extrinsic pathway funnels signals to the cell from its environmental context, while the intrinsic pathway tells the cell to die when it is under stress. Internal death stimuli include DNA damage, unfolded proteins, reactive oxygen species, oncogene activation, infection, toxic insult, and heat shock. Both pathways funnel through to the caspase proteins, which lie at the core of apoptosis by proteolytically cleaving their many targets to either deactivate them or give them specific apoptotic functions.

Caspases

The cysteine-dependent, aspartate-directed proteases (caspases) exist as zymogens when inactive. When conditions are favourable, (that is, during a death response,) procaspases dimerise and reciprocally activate by mutual proteolytic cleavage. The resulting caspases are then fully competent to cleave its downstream targets.

There are two types of caspase: initiators and executioners. Initiator caspases are the first ones to respond to the death signal, and their activity is to activate other caspases - both initiators and executioners. They contain CARDs (caspase recruitment domains) and DEDs (death execution domains). Executioner caspases have many downstream targets which are responsible for the morphological changes that apoptotic cells undergo. For example, executioner caspases can target cell-cell and cell-extracellular matrix contacts, leading to detachment; they can target ROCK, activating its function to increase actinomyosin force and leading to blebbing; they can cleave nuclear lamin B, leading to nuclear envelope breakdown; and they can destroy the inhibitor of caspase-activated DNase (iCAD), allowing the caspase-activated DNase (CAD) to perform karyorrhexis.

Extrinsic activation

Two pathways in extrinsic activation of apoptosis are through the Fas receptor and the TNFα receptor. Signalling through a Fas ligand-bound Fas receptor leads to recruitment of FADD on the cytosolic face. FADD docks onto the Fas receptor through homotypic interactions between death domains (DDs). FADD also contains a DED, which recruits and concentrates procaspase 8, thereby leading to a caspase cascade. The last step is inhibited by FLIP, which competes with procaspase 8 for procaspase 8 binding. It blocks the formation of procaspase dimers, and so blocks the caspase cascade.

Signalling through a TNFα-bound TNFα receptor leads to recruitment of TRADD and assembly of complex I on the cytosolic face - also through a series of DD homotypic binding interactions. This can go one of two ways: it can be internalised, leading to release of complex I and processing into complex II. Complex II then uses its DDs to recruit FADD, where signals intersect with the Fas pathway. Alternatively, the receptor does not internalise, and complex I leads to signalling through NF-κB, which signals for survival, not apoptosis. cIAP disfavours complex II formation and promotes complex I retention.

Intrinsic activation

The intrinsic pathway involves leakage of cytochrome c via mitochrondial outer membrane permeabilisation (MOMP), formation of the apoptosome, and concentration of procaspase 9. In response to intrinsic death stimuli, homodimers of Bax and of Bak form pores in the mitochrondrial outer membrane. Cytochrome c is then allowed to leak out of the mitochondria and bind Apaf1. In the absence of cytochrome c, Apaf1 autoinhibits by interaction between its WD40 domains. In the presence of cytochrome c, Apaf1 is allowed to oligomerise, forming the apoptosome. This interaction reveals the CARD on Apaf1, and recruits and concentrates procaspase 9, leading to a caspase cascade.

There is regulation at each of these steps. Bcl-2 is an antiapoptotic protein, which disfavours homodimerisation of Bax and of Bak, thereby preventing the formation of pores. It does this by favouring the conformation of Bax and of Bak where their BH3 domain is hidden - it is through the BH3 domain that Bax anad Bak homodimerise. XIAP is another antiapoptotic protein which binds and sequesters caspases through its BIR (bacculovirus inhibitor of apoptosis (IAP) repeat) domain. Through its RING domain, it can recruit an E3 ubiqitin ligase, and mark its binding partners for proteasomal destruction. Finally, proapoptotic Smac (second mitochondria-derived activator of caspases) and DIABLO (direct IAP-binding protein with low pI) bind XIAP on its BIR domains, thereby inactivating it.

Immune system

Both cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells can induce cell death, by apoptosis or otherwise. T cells recognise cells decorated with major histocompatibility complexes (MHCs) which display foreign antigens. T cells provide the Fas ligand to these cells, ensuing death. If the cell does not have a Fas receptor, the T cell can invoke death by perforin and granzymes - perforin punches holes in the cell membrane while granzymes induce a caspase cascade, or can alternatively kill the cell independently of apoptosis.

Natural killer cells recognise MHC class I proteins on the surfaces of cells. They also recognise activating ligands on the cell surface which act to promote perforin/granzyme-induced death. The activatory signal is suppressed if the cell bears an MHC class I protein which is recognised as 'self' - absence of this elicits death by perforin and granzymes.

This infographic looks like candy. Please do not try to eat it. Happy Valentine's Day (for tomorrow)!

Further reading

Riedl, S.J.; Shi, Y. 2004. "Molecular mechanisms of caspase regulation during apoptosis." Nature Reviews Molecular Cell Biology 5:897-907.

Trapani, J.A.; Smyth, M.J. 2002. "Functional significance of the perforin/granzyme cell death pathway." Nature Reviews Immunology 2:735-747.

Ljunggren, H.-G.; Malmberg, K.-J. 2007. "Prospects for the use of NK cells in immunotherapy of human cancer." Nature Reviews Immunology 7:329-339.

Holcik, M.; Korneluk, R.G. 2001. "XIAP, the guardian angel." Nature Reviews Molecular Cell Biology 2:550-556.