A RIPK3-caspase 8 complex mediates atypical pro-IL-1β processing.

Journal Article (Journal Article)

Caspase 8, the initiator caspase for death receptor-induced apoptosis, functions as a negative regulator of receptor interacting protein kinase 3 (RIPK3), an essential factor for TNF-, TLR3-, and TLR4-induced necroptosis. In certain situations, caspase 8 can also participate in pro-IL-1β processing. However, the biochemical complex that mediates caspase 8-mediated processing is not defined. In this study, we show that RIPK3 is crucial for caspase 1- and caspase 8-mediated pro-IL-1β and pro-IL-18 processing in bone marrow-derived dendritic cells (BMDCs) in response to LPS stimulation. Caspase 8-mediated pro-IL-1β processing requires intact RIPK1, RIPK3, TRIF, and FADD. In response to LPS, a complex that contains RIPK1, RIPK3, FADD, and caspase 8 is formed. Surprisingly, RIPK3-specific kinase inhibitors strongly enhanced caspase 8 activation and pro-IL-1β processing in LPS-stimulated BMDCs. However, studies in BMDCs expressing the kinase-inactive RIPK3-K51A mutant or RIPK1-K45A mutant showed that the kinase activity of neither RIPK1 nor RIPK3 is required for LPS-induced caspase 8 activation and IL-1β secretion. Hence, RIPK3 is an unexpected positive regulator of caspase 8 activity that promotes IL-1β maturation in BMDCs.

Full Text

Duke Authors

Cited Authors

  • Moriwaki, K; Bertin, J; Gough, PJ; Chan, FK-M

Published Date

  • February 15, 2015

Published In

Volume / Issue

  • 194 / 4

Start / End Page

  • 1938 - 1944

PubMed ID

  • 25567679

Pubmed Central ID

  • PMC4324020

Electronic International Standard Serial Number (EISSN)

  • 1550-6606

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.1402167


  • eng

Conference Location

  • United States