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Figure 1: Mechanism of tumour necrosis factor-α (TNF-α) induced necroptosis. Binding of TNF-α to its receptor results in formation of Complex I.
Activation of cIAP and tartrate resistant acid phosphatase activates downstream NF-κB signaling and subsequently promote cell survival. Complex II
acts as a switch between apoptosis and necroptosis. Activation of caspase-8 guides the cells to apoptosis. Inhibition of caspase-8 leads to formation of
a necrosome. Membrane translocation of phosphrylated MLKL disrupts cell membrane. The mechanisms underlying the lysis of cytoplasmic contents
during necrosis are still unclear. DAMPs: damage associated molecular patterns; MLKL: mixed lineage kinase domain-like protein; TNF: tumour necrosis
factor; TNFR: tumour necrosis factor receptor; cIAP: calf intestinal alkaline phosphatise; TRADD: tumor necrosis factor receptor associated death
domain; TRAF: TNFR-associated factors; RIP1: receptor-interacting protein 1; CYLD: cylindromatosis; Casp8: caspase-8; RIP3: receptor-interacting
protein 3; NF-kB: nuclear factor kappa.
death”. Necrosis, however, has long been thought as (TNF-α) induced necroptosis. Necroptosis is initiated
acute and uncontrollable, largely owning to its elusive when death signals such as TNF-α and Fas bind to
molecular mechanism, and thus been thought as “un- their membrane receptors. This ligation leads to the
programmed”. formation of a membrane associated protein complex,
named complex I. Complex I is composed by: (1)
[4]
In the year of 2005, Dr. Jun-Ying Yuan at Harvard proteins which have a death domain such as tumor
[2]
University reported a novel type of necrosis, which necrosis factor receptor (TNFR)-associated death
occurred in cells when the apoptosis machinery is domain (TRADD), Fas-associated death domain
inhibited, but extracellular apoptotic stimulation (FADD); (2) RIP1; (3) TNFR-associated factors (TRAF),
persisted. This type of necrosis can be inhibited such as TRAF2 or TRAF5, and (4) cellular inhibitor
by a chemical named Necrostatin-1 (Nec-1), which of apoptosis protein 1 (cIAP1) and cIAP2. TRADD
[5]
suppresses the activity of receptor-interacting acts as an adaptor for recruiting RIP1 to TNFR1.
protein 1 (RIP1), suggesting that the cell death is Subsequently, TRAF2/3/5 and cIAPs are added into the
molecularly regulated. Because the dying cells the protein complex. If E3 ubiquitin ligase is activated,
[6]
researchers originally identified showed a mixture of TRAF2/5 and cIAP1/2 can ubiquitinate RIP1, which
ultrastructural features of both apoptosis and necrosis, results in stabilization of the RIP1-containing plasma
for example, condensation of chromatin, disruption of membrane associated complex that activates nuclear
the cell membrane and lysis of cytoplasmic contents, it factor kappa and mitogen-activated protein kinases,
was termed as necroptosis (necrosis + apoptosis). Later and thus promoting cell survival. Therefore, protein
[7]
on, it was found to show mostly the morphological complex I determines the fate of cells to either survival
features of unregulated necrotic death. [3] or death. [8]
MOLECULAR MECHANISM OF NECROPTOSIS Activation of necroptosis signalling starts with
deubiquitination of RIP1 and other components by
Since Dr. Yuan’s publication, many studies have been deubiquitinating enzyme cylindromatosis, which
performed on the occurrence and molecular mechanism removes ubiquitin chains from RIP1, thus, destabilizing
of necroptosis. Most of the current knowledge about Complex I. Deubiquitinated RIP1 is released from
[9]
necroptosis comes from tumour necrosis factor α Complex I and combines with FADD, TRADD,
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