Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1

Parkin (Park2), a RING-between-RING-type E3 ubiquitin ligase, has been implicated in regulating NF-kappa B. Mutations in Parkin are associated with Parkinson's disease. Here we investigated the interaction of Parkin with Receptor-interacting protein kinase 1 (RIPK1) kinase, a key mediator of multiple signaling pathways activated by TNFR1 including NF-kappa B pathway. We report that Parkin interacts with RIPK1 and mediates K63 ubiquitination of RIPK1 on K376 in TNFR1-signaling pathway. The expression of Parkin promotes the recruitment of transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1), nuclear factor-kappa B (NF-kappa B) essential molecule (NEMO), Sharpin and A20 in complex I associated with TNFR1 upon TNF alpha stimulation. Ubiquitination of RIPK1 by Parkin increases the activation of NF-kappa B and mitogen-activated protein kinases (MAPKs) by promoting the phosphorylation of inhibitor of kappa B kinase (IKK)alpha/beta and I kappa B alpha and nuclear translocation of p65. Thus, we conclude that Parkin modulates the K63 ubiquitination status of RIPK1 to promote the activation of NF-kappa B and MAPKs.