Accelerating Discovery



MISSION: This laboratory focuses on understanding the molecular programs underlying the adaptation of cells to perturbations on organelle function, its relationship to pathological conditions affecting the nervous system, and the development of prototypic therapies to prevent this damage.

Proteostasis networks and ER stress - Alterations in protein homeostasis (referred to as proteostasis) have devastating consequences for the proper function of the cell. Stress injuries initiate multiple signaling responses, either to adapt to the new condition or to activate specific apoptosis pathways if a critical threshold of damage has been reached. Our laboratory is committed to the study cellular strategies involved in adaptation to chronic organelle damage, which are linked to several brain diseases. The endoplasmic reticulum (ER) has important functions to sustain proteostasis, highlighting its role as a sophisticated machinery for folding, quality control, and secretion of proteins. Alterations on ER function lead to the accumulation of unfolded proteins at its lumen, a cellular condition termed “ER stress”. ER stress engages an integrated signaling pathway known as the “Unfolded Protein Response (UPR), which aims to restore homeostasis. Nevertheless, the mechanisms that control the transition from an adaptive state to cell death programs remain poorly understood and are a central subject of our research.

The UPRosome
How do cells sense protein folding stress? ER stress stimulates distinct stress sensors including IRE1, PERK and ATF6. IRE1 is part of the most conserved signalling branch of the UPR and harbors kinase and endoribonuclease (RNAse) activities within its cytosolic domain. IRE1 multimerization leads to the trans-autophosphorylation of its cytosolic domain, activating the RNAse domain. Active IRE1 processes the mRNA of X‑Box binding protein-1 (XBP-1), shifting its codon reading frame with resultant expression of an active transcription factor (XBP-1s). XBP-1 mediates the upregulation of crucial UPR-related genes involved in folding, secretion, ER biogenesis, protein quality control and autophagy. Under prolonged ER stress, IRE1 signaling is turn-off to shift cells into an apoptosis program. We have identified several components that control of the kinetics of IRE1 signaling through the assembling a large signaling complex. We have termed this platform the UPRosome (Hetz 2012 Nat Rev Mol Cell Biol), where IRE1 signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble.
Our group have identified components that controls the activation of IRE1 (Hetz el at., 2006 Science, Gupta el al, 2010 PLoS Biol), that attenuates UPR signaling (Lisbona et al., 2009 Mol Cell), or help maintained the sustained activation (Rodriguez et al., 2012, EMBO J). In addition we described novel connections between the ER stress signaling and the autophagy pathway through modulation of components of the UPRosome (Castillo et al., 2010 EMBO J). We are currently describing the dynamics of the UPRosome using proteomics, interactome studies and RNAi screenings.

A multidisciplinary approach

Overall, our laboratory have used multiple model system to understand how the UPR is regulated and what determines the transition from adaptation to cell death programs. We have published many studies using complementary approaches from biochemical, cell biology and in vivo strategies to attack this central question. On a recent study we discovered a new conserved regulator of ER stress-mediated apoptosis, termed GRINA/TMBIM3 (Rojas et al., 2012 Cell Death Diff), which is a member if a new group of conserved cell death regulators termed the “Bax inhibitor (BI-1) or TMBIM family”. This study illustrates the holistic view of our research because we combined mouse, zebra fish and Drosophila models to define an evolutionary-conserved anti-apoptotic activity of GRINA/TMBIM3. At the molecular levels we showed that this gene is a novel target of the UPR and regulates ER calcium homeostasis. We have developed other studies to investigate the function of BI-1/TMBIM6 in ER stress and autophagy processes using mouse and drosophila models (Castillo et al., 2010 EMBO J and Lisbona et al., 2009 Mol Cell). We have also contributed to define novel apoptosis pathways under ER stress that are independent of the BCL-2 family of proteins (Zamorano et al., 2012 PLoS One).

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Hetz Lab © 2012 | Laboratory of Cellular Stress and Biomedicine | Design NV