[HTML][HTML] RIPK1-and RIPK3-induced cell death mode is determined by target availability

WD Cook, DM Moujalled, TJ Ralph, P Lock… - Cell Death & …, 2014 - nature.com
WD Cook, DM Moujalled, TJ Ralph, P Lock, SN Young, JM Murphy, DL Vaux
Cell Death & Differentiation, 2014nature.com
Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following
death receptor ligation. To study the requirements for RIPK-triggered cell death in the
absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3
that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF
or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell
death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death …
Abstract
Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a ‘switch’operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins.
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