ALFARO CORTEZ, IVAN ESTEBAN

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ALFARO CORTEZ, IVAN ESTEBAN
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ORCID
0000-0002-5938-5940
Scopus Author ID
24066581500
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    A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer
    (2024)
    Yanara A. Bernal
    ;
    Alejandro Blanco
    ;
    Eduardo A. Sagredo
    ;
    Karen OrĂłstica  
    ;
    ALFARO CORTEZ, IVAN ESTEBAN  
    Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.
    Scopus© Citations 4  7
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    Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation
    (2019)
    Andro Montoya
    ;
    Daniela Elgueta
    ;
    Javier Campos
    ;
    Ornella Chovar
    ;
    Paulina FalcĂłn
    Scopus© Citations 54  4
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    Palmitic and Stearic Acids Inhibit Chaperone-Mediated Autophagy (CMA) in POMC-like Neurons In Vitro
    (2022)
    Rodrigo Espinosa
    ;
    Karla Gutiérrez
    ;
    Javiera Rios
    ;
    Fernando Ormeño
    ;
    Liliana Yantén
    <jats:p>The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. Autophagy is a lysosomal-degrading pathway that can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Previous studies showed that PA impairs macroautophagy function and insulin response in hypothalamic proopiomelanocortin (POMC) neurons. Here, we show in vitro that the exposure of POMC neurons to PA or SA also inhibits CMA, possibly by decreasing the total and lysosomal LAMP2A protein levels. Proteomics of lysosomes from PA- and SA-treated cells showed that the inhibition of CMA could impact vesicle formation and trafficking, mitochondrial components, and insulin response, among others. Finally, we show that CMA activity is important for regulating the insulin response in POMC hypothalamic neurons. These in vitro results demonstrate that CMA is inhibited by PA and SA in POMC-like neurons, giving an overview of the CMA-dependent cellular pathways that could be affected by such inhibition and opening a door for in vivo studies of CMA in the context of the hypothalamus and obesity.</jats:p>
    Scopus© Citations 7  3
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    Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
    (2022)
    Ainoa Fernández-Olivares
    ;
    Eduardo Durán-Jara
    ;
    Daniel A. Verdugo
    ;
    Mariana C. Fiori
    ;
    Guillermo A. Altenberg
    <jats:p>Connexin (Cxs) hemichannels participate in several physiological and pathological processes, but the molecular mechanisms that control their gating remain elusive. We aimed at determining the role of extracellular cysteines (Cys) in the gating and function of Cx46 hemichannels. We studied Cx46 and mutated all of its extracellular Cys to alanine (Ala) (one at a time) and studied the effects of the Cys mutations on Cx46 expression, localization, and hemichannel activity. Wild-type Cx46 and Cys mutants were expressed at comparable levels, with similar cellular localization. However, functional experiments showed that hemichannels formed by the Cys mutants did not open either in response to membrane depolarization or removal of extracellular divalent cations. Molecular-dynamics simulations showed that Cys mutants may show a possible alteration in the electrostatic potential of the hemichannel pore and an altered disposition of important residues that could contribute to the selectivity and voltage dependency in the hemichannels. Replacement of extracellular Cys resulted in “permanently closed hemichannels”, which is congruent with the inhibition of the Cx46 hemichannel by lipid peroxides, through the oxidation of extracellular Cys. These results point to the modification of extracellular Cys as potential targets for the treatment of Cx46-hemichannel associated pathologies, such as cataracts and cancer, and may shed light into the gating mechanisms of other Cx hemichannels.</jats:p>
    Scopus© Citations 6  2
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    Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control
    (2022)
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    ;
    Francisco Saavedra
    ;
    Claudia Espinoza-Arratia
    ;
    Nicolas W Martinez
    ;
    Tatiana Cruces
    <jats:title>Abstract</jats:title> <jats:p>Although there are several pathways to ensure that proteins are folded properly in the cell, little is known about the molecular mechanisms regulating histone folding and proteostasis. In this work, we identified that chaperone-mediated autophagy (CMA) is the main pathway involved in the degradation of newly synthesized histones H3 and H4. This degradation is finely regulated by the interplay between HSC70 and tNASP, two histone interacting proteins. tNASP stabilizes histone H3 levels by blocking the direct transport of histone H3 into lysosomes. We further demonstrate that CMA degrades unfolded histone H3. Thus, we reveal that CMA is the main degradation pathway involved in the quality control of histone biogenesis, evidencing an additional mechanism in the intricate network of histone cellular proteostasis.</jats:p>
    Scopus© Citations 8  4
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    Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
    (Springer Science and Business Media LLC, 2025-03-27)
    Ainoa Fernández-Olivares
    ;
    Viviana P Orellana
    ;
    JesĂşs Llanquinao
    ;
    NUĂ‘EZ VASQUEZ, GONZALO ESTEBAN  
    ;
    Pablo PĂ©rez-Moreno
    Scopus© Citations 1  10
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    PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner
    (Elsevier BV, 2025-11)
    Nicolás W. Martínez
    ;
    Felipe GĂłmez
    ;
    Ariel Tapia-Godoy
    ;
    Juan Francisco Roa
    ;
    Fernanda Moreso-Contreras
    Scopus© Citations 2  2
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    Scopus© Citations 49  2
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    KFERQ-selective protein autophagy in Caenorhabditis elegans depends on LMP-1
    (Public Library of Science (PLoS), 2025-09-02)
    Alicia N. Minniti
    ;
    MarĂ­a Gallardo-Campos
    ;
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    ;
    NUĂ‘EZ VASQUEZ, GONZALO ESTEBAN  
    ;
    Carlos F. Lagos
    Mammalian cells exhibit three autophagy mechanisms: macroautophagy, microautophagy (MIA), and chaperone-mediated autophagy (CMA), each employing unique mechanisms for transporting cellular material to the lysosome for degradation. MIA involves the engulfment of proteins via lysosomes/late endosomes through membrane invagination, while CMA directly imports cytosolic proteins into lysosomes, selectively targeting those harboring the KFERQ pentapeptide motif, helped by the chaperone HSC70. Despite the identification of several genetic markers of these pathways, our understanding of the underlying mechanisms, particularly in MIA and CMA, remains limited. To study CMA in vivo we designed a photoactivatable CMA reporter consisting of a plasmid encoding the KFERQ consensus signal for CMA targeting. We generated transgenic <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> strains with diverse genetic backgrounds to analyze the role of known molecular components of CMA in mammals. Additionally, we conducted an in-silico analysis of the structural interaction between <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> LMP-1 or LMP-2 proteins with the HSP-1 chaperone. Results: Our study shows a significant alteration in the distribution pattern of the KFERQ reporter in muscle cells upon induction of selective autophagy (CMA or MIA). We found that the reporter localized into lysosomes only during starvation, which abrogated in the absence of LMP-1. This study validates CMA in <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> and provides the development of a new tool for understanding selective autophagy mechanisms and their potential implications in various organisms.
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