The death-inducing activity of RIPK1 is regulated by the pH environment.

Journal Article (Journal Article)

Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase that dictates whether cells survive or die in response to the cytokine tumor necrosis factor (TNF) and other inflammatory stimuli. The activity of RIPK1 is tightly controlled by multiple posttranslational modification mechanisms, including ubiquitination and phosphorylation. Here, we report that sensitivity to TNF-induced, RIPK1-dependent cell death was tunable by the pH environment. We found that an acidic extracellular pH, which led to a concomitant decrease in intracellular pH, impaired the kinase activation of RIPK1 and autophosphorylation at Ser166 Consequently, formation of the cytosolic death-inducing complex II and subsequent RIPK1-dependent necroptosis and apoptosis were inhibited. By contrast, low pH did not affect the formation of membrane-anchored TNFR1-containing signaling complex (complex I), RIPK1 ubiquitination, and NF-κB activation. TNF-induced cell death in Ripk1 -/- cells was not sensitive to pH changes. Furthermore, mutation of the conserved His151 abolished the pH dependence of RIPK1 activation, suggesting that this histidine residue functions as a proton acceptor to modulate RIPK1 activity in response to pH changes. These results revealed an unexpected environmental factor that controls the death-inducing activity of RIPK1.

Full Text

Duke Authors

Cited Authors

  • Moriwaki, K; Balaji, S; Ka-Ming Chan, F

Published Date

  • May 12, 2020

Published In

Volume / Issue

  • 13 / 631

PubMed ID

  • 32398349

Pubmed Central ID

  • PMC7337977

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

Digital Object Identifier (DOI)

  • 10.1126/scisignal.aay7066


  • eng

Conference Location

  • United States