Browsing by Author "Hetz, Claudio"

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    BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response
    (2011) Castillo, Karen; Rojas-Rivera, Diego; Lisbona, Fernanda; Caballero, Benjamin; Nassif, Melissa; Court, Felipe A.; Schuck, Sebastian; Ibar, Consuelo; Walter, Peter; Sierralta, Jimena; Glavic, Alvaro; Hetz, Claudio
    Both autophagy and apoptosis are tightly regulated processes playing a central role in tissue homeostasis. Bax inhibitor 1 (BI-1) is a highly conserved protein with a dual role in apoptosis and endoplasmic reticulum (ER) stress signalling through the regulation of the ER stress sensor inositol requiring kinase 1 alpha (IRE1 alpha). Here, we describe a novel function of BI-1 in the modulation of autophagy. BI-1-deficient cells presented a faster and stronger induction of autophagy, increasing LC3 flux and autophagosome formation. These effects were associated with enhanced cell survival under nutrient deprivation. Repression of autophagy by BI-1 was dependent on cJun-N terminal kinase (JNK) and IRE1 alpha expression, possibly due to a displacement of TNF-receptor associated factor-2 (TRAF2) from IRE1 alpha. Targeting BI-1 expression in flies altered autophagy fluxes and salivary gland degradation. BI-1 deficiency increased flies survival under fasting conditions. Increased expression of autophagy indicators was observed in the liver and kidney of bi-1-deficient mice. In summary, we identify a novel function of BI-1 in multicellular organisms, and suggest a critical role of BI-1 as a stress integrator that modulates autophagy levels and other interconnected homeostatic processes. The EMBO Journal (2011) 30, 4465-4478. doi:10.1038/emboj.2011.318; Published online 16 September 2011
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    Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
    (2020) Dufey, Estefanie; Bravo-San Pedro, Jose Manuel; Eggers, Cristian; Gonzalez-Quiroz, Matias; Urra, Hery; Sagredo, Alfredo, I; Sepulveda, Denisse; Pihan, Philippe; Carreras-Sureda, Amado; Hazari, Younis; Sagredo, Eduardo A.; Gutierrez, Daniela; Valls, Cristian; Papaioannou, Alexandra; Acosta-Alvear, Diego; Campos, Gisela; Domingos, Pedro M.; Pedeux, Remy; Chevet, Eric; Alvarez, Alejandra; Godoy, Patricio; Walter, Peter; Glavic, Alvaro; Kroemer, Guido; Hetz, Claudio
    The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1 alpha under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1 alpha signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1 alpha -dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1 alpha endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1 alpha to catalyze RIDD. The protective role of IRE1 alpha under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis. IRE1 alpha plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1 alpha is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.
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    Lack of Activation of the Unfolded Protein Response in Mouse and Cellular Models of Niemann-Pick Type C Disease
    (2011) Klein Posternack, Andrés David; Mosqueira Montero, Matías José; Martínez, Gabriela; Robledo Plaza, Fermín Alberto; González Bustos, Marcela Paz; Caballero, Benjamín; Cancino Lobos, Gonzalo; Álvarez Rojas, Alejandra Beatriz; Hetz, Claudio; Zanlungo Matsuhiro, Silvana
    Background: Niemann-Pick type C (NPC) disease is a fatal lysosomal storage disease related to progressive neurode-generation secondary to abnormal intracellular accumulation of cholesterol. Signs of endoplasmic reticulum (ER) stress have been reported in other lipidoses. Adaptation to ER stress is mediated by the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates stress or triggers apoptosis of irreversibly damaged cells. Objective: To investigate the possible engagement of ER stress responses in NPC models. Methods: We used NPC1 deficient mice and an NPC cell-based model by knocking down the expression of NPC1 to measure several UPR markers through different approaches. Results: Despite expectations that the UPR will be activated in NPC, our results indicate a lack of ER stress reactions in the cerebellum of symptomatic mice. Similarly, knocking down NPC1 in Neuro2a cells leads to clear cholesterol accumulation without evidence of UPR activation. Conclusion: Our results suggest that cholesterol overload and neuronal dysfunction in NPC is not associated with ER stress, which contrasts with recent reports suggesting the activation of the UPR in other lysosomal storage diseases. Copyright (c) 2010 S. Karger AG, Basel
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    Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons
    (2010) Klein Posternack, Andrés David; Maldonado Vera, Carola Patricia; Vargas Rojas, Lina Marcela; González Bustos, Marcela Paz; Robledo Plaza, Fermín Alberto; Pérez de Arce Guzman, Karen Andrea; Muñoz, Francisco J.; Hetz, Claudio; Álvarez, Alejandra R.; Zanlungo Matsuhiro, Silvana
    Niemann-Pick type C (NPC) is a neurodegenerative disease characterized by the intralysosomal accumulation of cholesterol leading to neuronal apoptosis. We have previously reported the activation of the c-Abl/p73 proapoptotic pathway in the cerebellum of NPC mice; however, upstream signals underlying the engagement of this pathway remain unknown. Here, we investigate the possible role of oxidative stress in the activation of c-Abl/p73 using different in vitro and in vivo NPC models. Our results indicate a close temporal correlation between the appearance of nitrotyrosine (N-Tyr; a post-translational tyrosine modification caused by oxidative stress) and the activation of c-Abl/p73 in NPC models. To test the functional role of oxidative stress in NPC, we have treated NPC neurons with the antioxidant NAC and observed a dramatic decrease of c-Abl/p73 activation and a reduction in the levels of apoptosis in NPC models. In conclusion, our data suggest that oxidative stress is the main upstream stimulus activating the c-Abl/p73 pathway and neuronal apoptosis in NPC neurons.
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    The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease
    (2020) Onate, Maritza; Catenaccio, Alejandra; Salvadores, Natalia; Saquel, Cristian; Martinez, Alexis; Moreno-Gonzalez, Ines; Gamez, Nazaret; Soto, Paulina; Soto, Claudio; Hetz, Claudio; Court, Felipe A.
    Parkinson's disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine-dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in preclinical models of PD, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.