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Significance This study demonstrates a distinct mode of RIPK1 activation mediated by a detergent-insoluble, highly ubiquitinated, activated RIPK1 species (iuRIPK1) which functions as a critical intermediate between TNF-receptor-associated complex I and assembly of the cytosolic caspase activation platform complex II in RIPK1-dependent apoptosis (RDA). By conducting a systematic screen for RDA regulators, we reveal the regulation of iuRIPK1 by Parkinson’s disease (PD)-associated LRRK2, E3 ubiquitin ligase c-Cbl, and ALS-associated NEK1. These results point to possible mechanistic links between RIPK1-mediated apoptosis and neurodegenerative diseases such as ALS and PD.

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis