Secreted and membrane proteins are translocated into the Endoplasmic Reticulum (ER) in an unfolded state. The ER comprises many enzymes and chaperones that ensure productive protein folding. Different physiological and chemical factors that compromise ER homeostasis lead to ER stress. To cope with this situation, cells activate intracellular signaling pathways that are known as the unfolded protein response (UPR), which initially aims at restoring ER homeostasis. Like many other human diseases; some cancer types are associated with ER stress, UPR activation and accumulation of ER lumenal proteins in the cytosol.

Current Projects

Recently, we discovered an adaptive ER quality control system to debulk the ER during stress to restore homeostasis. We named this novel process -ER to CYtosol Signaling- "ERCYS". In cancer cells, constitutive ER stress leads to constitutive protein reflux from the ER to the cytosol. In the cytosol, refluxed proteins gain new functions to inhibit tumor suppressing signaling pathways. ERCYS functions to debulk the ER during protein folding stress, and serves as a mode of communication between the ER and the cytosol. In mammalian cells we found that ERCYS may function in parallel to ERAD, UPR and Pre-emptive Quality Control (Pre-QC) systems to manage the ER protein load. In my lab we are interested in 1. Understand at the molecular level the mechanism that control the reflux of ER lumenal proteins from the ER to the cytosol. 2. Study the pro-cancerous functions of the refluxed proteins in the cytosol and develop genetic and pharmacological strategies to tamper with their new activities in non-ER locations.

Daria Sicari, Raphael Pineau, Pierre-Jean Le Reste, Luc Negroni, Sophie Chat, Aiman Mohtar, Reynald Gillet, M. Ted Hupp, Eric Chevet and Aeid Igbaria Reflux of ER proteins to the cytosol is associated with the inactivation of tumor suppressors. BioRxiv 2020

Aeid Igbaria*, Philip I. Merksamer*, Ala Trusina, Firehiwot Tilahun, Jefferey R. Johnson, Onn Brandman, Nevan J. Krogan, Jonathan S. Weissman, Feroz R. Papa. (2019), Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress. Proc Natl Acad Sci U S A (PNAS), 2019.

Alise Ponsero*, Aeid Igbaria*, Maxwell A. Darch, Samia Miled, Caryn E. Outten, Jakob R. Winther, Benoit D’autreaux, Agnes Delaunay-Moisan and Michel B. Toledano. Endoplasmic reticulum transport of glutathione by Sec61 is regulated by Ero1 and Bip. Molecular Cell, 2017.

Rajarshi Ghosh., Likun Wang., Eric S. Wang., B. Gayani K. Perera, Aeid Igbaria, Shuhei Morita1, Kris Prado, Maike Thamsen, Deborah Caswell, Hector Macias1, Kurt F. Weiberth, Micah J. Gliedt, Marcel V. Alavi, Sanjay B. Hari, Arinjay K. Mitra, Barun Bhhatarai, Stephan C. Schürer, Erik L. Snapp, Douglas B. Gould, Michael S. German, Bradley J. Backes, Dustin J. Maly, Scott A. Oakes, Feroz R. Papa. Allosteric inhibition of the IRE1 RNase preserves cell viability and function during endoplasmic reticulum stress. Cell, 2014.

Kumar C*, Igbaria A*, D'Autreaux B, Planson AG, Junot C, Godat E, Bachhawat AK, Delaunay-Moisan A, Toledano MB. Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control. EMBO J, 2011.