![]() ![]() This review focuses on proteins functioning at ER-PM contact sites and highlights the recent progress in their mechanisms and physiological roles. The physiological roles of ER-PM contact sites are dependent on a variety of regulators that individually or cooperatively perform functions in diverse cellular processes. Distinct tethering factors dynamically control the architecture of ER-PM junctions in response to intracellular signals or external stimuli. ![]() These ER-PM contact sites play essential roles in lipid homeostasis, ion dynamics, and cell signaling, which are carried out by protein-protein or protein-lipid interactions. The endoplasmic reticulum (ER) forms direct membrane contact sites with the plasma membrane (PM) in eukaryotic cells. 2Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, United States.1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.276, 20413–20418 (2001).Chenlu Li 1, Tiantian Qian 1, Ruyue He 1, Chun Wan 2, Yinghui Liu 1 * and Haijia Yu 1 * Nagasawa, M., Kanzaki, M., Iino, Y., Morishita, Y. Kuum, M., Veksler, V., Liiv, J., Ventura-Clapier, R. These cellular phenotypes are accompanied by hind leg weakness, trunk shaking, tail flagging, abnormal gaits, and ataxia in Clcc1(K298A) knock-in mice. They find enhanced ER stress in all these neuronal types as well as prominent degeneration of motoneurons. To test this idea, the authors monitor BiP and ubiquitin staining, both hallmarks of ER stress, in cerebellar granule cells, dentate gyrus neurons, and motoneurons of K298A knock-in mice. These results suggest that reduction of function of CLCC1 may cause ER stress. Guo and colleagues notice that the volume of the ER is enlarged in cells in which CLCC1 is knocked down and in cells expressing CLCC1(K298A), a mutant identified in this study that does not respond to PIP2 with enhanced channel activity (Fig. The UPR consequently engages signaling pathways that try to compensate for the damage. Disturbance of ER protein folding due to either external stress or malfunction of ER homeostasis triggers ER stress and activation of the unfolded protein response (UPR). This result is consistent with the function of a postulated charge neutralizing Cl – efflux channel that needs to be engaged when luminal ER Ca 2+ concentration drops.Īs mentioned earlier, the ER is where secreted and membrane proteins are folded. The authors also show that CLCC1 current is inhibited by Ca 2+ in the trans compartment of the lipid bilayer, which corresponds to the ER lumen, and further identify two aspartic residues in the luminal N-terminus that are responsible for Ca 2+ inhibition (Fig. 11 In the first set of experiments, Guo and colleagues use immunocytochemistry, biochemical approaches, and electrophysiology to show that mouse and/or human CLCC1 colocalize with ER protein calnexin, form a protein complex composed of at least two subunits, and generate single channel and microscopic anion currents when reconstituted in the lipid bilayer. In this issue of Cell Research, using a combination of powerful and complementary techniques, Guo and colleagues provide evidence that Chloride Channel CLIC Like 1 (CLCC1), an ER-resident protein cloned more than 20 years ago, 10 is a mediator of Cl – efflux in the ER. ![]()
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