RIP3 Mediates Necroptotic Cell Death in Response to Acid Stimulation of ASIC1a

Abstract

Acidosis occurs commonly under pathological conditions when body homeostasis is disrupted due to inflammation, hypoxia, cancer and other illnesses. However, the effects of acidosis on cell fates differ dramatically from one cell type to another. On one hand, acidosis is usually harmful to brain neurons, which are particularly sensitive to tissue acidosis that occurs very often among neurological disorders, including ischemic stroke. Because of this, acidotoxicity represents one of the major causes of neurodegeneration and brain injury. On the other hand, cancer cells thrive in acidity as the microenvironment of tumor is often acidic. Previously, we have shown that extracellular acid induces neuronal cell death through activation of acid-sensing ion channel isoform 1a (ASIC1a) in a manner that involves recruitment and phosphorylation of receptor interacting protein 1 (RIP1), but independent of the ion channel function of ASIC1a. Here, we demonstrate that receptor interacting protein 3 (RIP3) is also critically required for acid-induced cell death and the presence of ASIC1a and/or RIP3 determines the nature of cellular responses to acidosis. Whereas both ASIC1a and RIP3 are expressed in neurons, at least one of them tends to be absent in many cancer cell lines. In the absence of RIP3, acidosis activated NF-κB signaling to promote survival of the tumor through ASIC1a. Re-introduction of RIP3 then converted the cancer cells to undergo necrosis in response to acidosis. Conversely, inhibiting RIP3 reduced both acid-induced death of mouse cortical neurons in vitro and brain infarction in mice elicited by middle cerebral artery occlusion in vivo. Our data also implicate the formation of necrosome downstream of ASIC1a/RIP1 in response to acidosis in the presence of RIP3. Thus, ASIC1a works similarly as conventional death receptors that regulate both cell survival and demise. Differently controlling RIP3 expression and function may be of therapeutic values in treating different diseases.