Periodic Reporting for period 4 - VOLSIGNAL (Volume regulation and extracellular signalling by anion channels)
Reporting period: 2022-04-01 to 2023-09-30
In another major breakthrough, we identified, using a sophisticated genome-wide siRNA screen, the protein constituting the acid-activated anion channel ASOR (4), closing another gap in our knowledge of anion channels. ASOR is a multimer of TMEM206 proteins. We already identified pore residues and showed that it plays a role in acid-induced cell death (4). In collaboration with Steve Long, we obtained for the first time the structure of the open channel, which involves a highly unusual metamorphosis of the transmembrane domains, and clarified the activation by extracellular/luminal protons (9). Further, we identified a crucial cell biological role of ASOR: It provides the Cl- conductance that is needed in parallel to a TPC channel-mediated Na+ conductance for the shrinkage of macropinosomes (7). This shrinkage is crucial for downstream trafficking steps. As a consequence, RAS-mutant tumor cells grew better when TMEM206 was disrupted because they could use albumin, that is taken up by macropinocytosis, more efficiently (7).
The discovery of TMEM206 as constituting the ASOR channel, which has been known physiologically for about 10 years, but whose molecular identity has remained obscure, is a major breakthrough that now opens the door to analyze its structure-function relationship and, more importantly, its role in physiology and pathology. Indeed, in the few years after its discovery we already identified in cryo-EM studies the novel mechanism by which acidification causes a dramatic change in transmembrane toplogy that leads to channel opening. We also identified a crucial role in macropinocytosis that may be relevant for cancer. Using our mouse model, we pursue studies on the role of ASOR in endocytic processes at the organismal level in various tissues.