Necroptosis NOH HYUN JIN Cell Death Normal Cell

Necroptosis NOH HYUN JIN

Cell Death Normal Cell Apoptosis Autophagy Necrosis

Cell Death

N ENGL J MED 370; 5 2014 As early as the mid-19 th century, Rudolf Virchow taught that necrosis is a recognizable form of cell death; since then, pathologists have identified necrosis as both a cause and a consequence of disease. A century later, another form of cell death, apoptosis, was defined, and we now understand that this process is driven by a set of molecular mechanisms that “programs” the cell to die. It has often been assumed that necrosis is distinct from apoptosis, in part because of the belief that necrosis is not programmed by molecular events. It is now clear, however, that in some contexts, necrotic cell death can be driven by defined molecular pathways.

Evolution of the Concept of Programmed Necrosis In some cell types, FAS can trigger non-apoptotic cell death that is independent of caspases but dependent on the adaptor protein FADD and the presence and enzymatic activity of the protein kinase RIP 1. This milestone paper is the first report of RIP 1‑dependent necroptosis. Nature Immunol, 200, 1: 489 -495, Tschopp’s group

Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chem. Biol. 1, 112– 119 -- Degterev et al. identify Necrostatin-1 (Nec-1) as a potent inhibitor of TNF mediated necrosis and introduce the term “necroptosis”.

Identification of RIP 3 as a modulator of Necroptosis 2009 2014 ü In contrast to RIP 1, the loss of murine RIP 3 results in no significant phenotypic defect, and has allowed the role of RIP 3, and potentially necroptosis, to be examined in vivo during pathogenic infection and inflammatory disease models

Identification of MLKL as a modulator of Necroptosis Identification of MLKL as a key modulator of necroptosis 2012 2014 NSA: necrosulfonamide

Molecular pathways for Necroptosis

TNFR 1 -mediated necroptosis : the prototype of regulated necrosis

Relationship between TRAF 2 and TRADD - Cell line : He. La(RIP 3) - DNA plasmid: p. EGF-c 1, GFP-TRAF 2, GFP-Peliino (each 1 ug) - Transfection time: 24 h, 48 h - Transfection reagent: PEI GFP-Pellino GFP-TRAF 2 PEI (48 h) p. EGF-c 1 GFP-Pellino GFP-TRAF 2 p. EGF-c 1 PEI (24 h) GFP-TRAF 2 GFP-Pellino GFP TRADD Actin

Relationship between TRAF 2 and TRADD - Cell line : He. La(RIP 3) - DNA plasmid: p. EGF-c 1, GFP-TRAF 2, GFP-Peliino (each 1 ug) - Transfection time: 24 h, 36 h, 48 h - Transfection reagent: PEI He. La (RIP 3) GFP-Pellino GFP-TRAF 2 p. EGF-c 1 GFP-Pellino GFP-TRAF 2 PEI (36 h) p. EGF-c 1 GFP-Pellino GFP-TRAF 2 PEI (48 h) p. EGF-c 1 GFP-Pellino GFP-TRAF 2 p. EGF-c 1 PEI (24 h) He. La (RIP 3) GFP-TRAF 2 GFP-Pellino GFP TRADD (short) TRADD (long) Actin (short) Actin (long)

What is RIP 3 -mediated MLKL activator under the ER stress condition induced by thapsigargin?

What is RIP 3 -mediated MLKL activator under the ER stress condition induced by thapsigargin?

What is RIP 3 -mediated MLKL activator under the ER stress condition induced by thapsigargin? - Thapsigargin (TG) condition : 9 h / 1, 2 (u. M) He. La (RIP 3) TG - 1 TG 2 - 1 2 p. MLKL RIP 3 CHOP MLKL Actin

What is RIP 3 -mediated MLKL activator under the ER stress condition induced by thapsigargin? - Thapsigargin (TG) condition : 2 u. M / 0, 3 h, 6 h, 9 h, 12 h He. La (NC) He. La (RIP 3) TG - 3 6 TG 9 12 (h) - 3 6 9 12 (h) p. MLKL (short) p. MLKL (long) CHOP MLKL Actin

What is RIP 3 -mediated MLKL activator under the ER stress condition induced by thapsigargin? - Thapsigargin (TG) condition : 12 h / 0, 0. 5, 1, 2, 4 (u. M ) He. La (RIP 3) TG - 0. 5 1 2 4 (u. M) p. MLKL (short) p. MLKL (long) CHOP MLKL Actin (short) Actin (long)

What is RIP 3 -mediated MLKL activator under the glucose deprivation condition? He. La (RIP 3) GD - 12 24 GD - 12 He. La (RIP 3) 24 GD p. MLKL (short) - - 12 24 He. La (NC) p. MLKL (long) p. MLKL RIP 3 RIP 1 (short) RIP 1 (long) Actin