Identification of RIP1 kinase as a specific cellular target of necrostatins.
Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.
Degterev
Alexei
A
Tufts University, School of Medicine, Department of Biochemistry, 136 Harrison Avenue, Boston, Massachusetts 02111, USA. alexei.degterev@tufts.edu
Hitomi
Junichi
J
Germscheid
Megan
M
Ch'en
Irene L
IL
Korkina
Olga
O
Teng
Xin
X
Abbott
Derek
D
Cuny
Gregory D
GD
Yuan
Chengye
C
Wagner
Gerhard
G
Hedrick
Stephen M
SM
Gerber
Scott A
SA
Lugovskoy
Alexey
A
Yuan
Junying
J
D000818:Animals; D017209:Apoptosis; D007093:Imidazoles / Q000378:metabolism*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases