Research ArticleCell Biology

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

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Science Signaling  12 May 2020:
Vol. 13, Issue 631, eaay7066
DOI: 10.1126/scisignal.aay7066

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Cell death on acid

The serine/threonine kinase RIPK1 is a critical mediator of cell death in response to the proinflammatory cytokine TNF. RIPK1 inhibitors are being investigated for the treatment of various infectious and inflammatory diseases. Moriwaki et al. found that the acidification that occurs in high-density cell cultures inhibited the kinase activity of RIPK1 and TNF-induced cell death. The effect of pH on RIPK1 activity was reversible and required histidine residues, which become protonated under low pH. These results suggest that cells in pathological situations in which intracellular pH becomes acidic are more resistant to RIPK1-dependent cell death.


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.

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