Myriah Acuña - Academia.edu (original) (raw)

Papers by Myriah Acuña

This journey has not been easy by any means necessary, however without the help and guidance of t... more This journey has not been easy by any means necessary, however without the help and guidance of the many people in my life, it simply would not have been possible and nothing that comes easy is ever worth having. My first appreciation is directed towards my mentor, Dr. German Rosas-Acosta, for not only his incredible knowledge, expertise and simple fascination for all the scientific disciplines which has continued to inspire my own; but also, his attitude and outlook on life which has given me hope even on the darkest days. Secondly, I would like to thank my committee: Dr. Manuel Llano for simply wanting to help me achieve this goal by any means which is quite refreshing and has meant the world to me. Dr. Xiao, for taking this project on without hesitation and together giving me truly valuable advice on the directions I should take. Another enormous thank you to the UTEP SUMO/Influenza laboratory and all who work there for the unfailing help and contribution of statistical analysis: Carlos Ontiveros, the laughs, encouragement and understanding: Arely Diaz and Sullenly Medina, and lastly, Amie Kern for having my back and the continuous support. I would also like to extend a thank you to Miguel Beltran, who patiently taught me most of what I know, who always lends a helping hand in whatever materials I need, who tells me exactly what I need to hear even if it's not what I want to hear, and the dire editing of this thesis. I would also like to thank Cynthia Carreon, we finished our undergraduate journey together, embarked on graduate school together and are now finishing together as well. This journey would be truly lonely without your help and light. Without the continuous love and support of one person in particular, none of this would be possible and that is my father. He's been my biggest fan and always encourages me to aim for the stars, reminding me that anything is possible with pure focus, commitment and sheer will. My friends have meant the world to me whom I truly regard as my family: Yuridia, Amanda and Daniel who always lend a listening ear, give nothing but constant positivity and never let me forget how much they truly believe in me. Lastly, I would like to thank my coaches: Cristobal and Andy, as well as all of my team mates at 10th Planet JiuJitsu , you have helped me accomplish this in more ways than you will ever know by simply showing me no situation is permanent and perseverance conquers all.

Scientific Reports

Substantial increases in the conjugation of the main human SUMO paralogs, SUMO1, SUMO2, and SUMO3... more Substantial increases in the conjugation of the main human SUMO paralogs, SUMO1, SUMO2, and SUMO3, are observed upon exposure to different cellular stressors, and such increases are considered important to facilitate cell survival to stress. Despite their critical cellular role, little is known about how the levels of the SUMO modifiers are regulated in the cell, particularly as it relates to the changes observed upon stress. Here we characterize the contribution of alternative splicing towards regulating the expression of the main human SUMO paralogs under normalcy and three different stress conditions, heat-shock, cold-shock, and Influenza A Virus infection. Our data reveal that the normally spliced transcript variants are the predominant mature mRNAs produced from the SUMO genes and that the transcript coding for SUMO2 is by far the most abundant of all. We also provide evidence that alternatively spliced transcripts coding for protein isoforms of the prototypical SUMO proteins, ...

SUMOylation, the covalent attachment of a Small Ubiquitin-like MOdifier (SUMO) to a protein targe... more SUMOylation, the covalent attachment of a Small Ubiquitin-like MOdifier (SUMO) to a protein target, involves four different enzymatic steps. First, the SUMO molecule must be proteolytically processed by SUMO peptidases/isopeptidases to cleave-off a short C-terminal sequence, thus exposing an internal di-Gly sequence that becomes the carboxyl end of the mature SUMO protein (i.e., the proteolytically processed form). Second, SUMO is activated in an ATP-dependent manner by SAE2/SAE1, the SUMO Activating Enzyme heterodimer. Activation results in SUMO forming sequential thioester bonds through its carboxyl di-Gly sequence, first with SAE2/SAE1 and subsequently with the SUMO conjugating enzyme, Ubc9. Third, SUMO is target-conjugated via the formation of an isopeptide bond with the-amino group of a Lys residue in the target protein, a process catalyzed by Ubc9. This step is frequently enhanced by the action of a SUMO ligase, which constitutes the fourth enzymatic activity involved in the pathway. SUMO ligases facilitate the formation of the isopeptide bond and provide some specificity to the process, as SUMO ligases are active over a relatively narrow range of protein targets. SUMOylated targets can subsequently become de-SUMOylated through the isopeptidase activity of de-SUMOylating enzymes. While there are only single SUMO activating and conjugating enzymes, there are numerous SUMO ligases and peptidases/isopeptidases. As for the actual SUMO modifier, there are five SUMO modifiers in humans, namely SUMO1, SUMO2, SUMO3, SUMO4, and SUMO5, each encoded by a separate gene (reviewed in 1-6). The SUMO genes likely arose via successive gene duplication events, as deduced from their phylogenetic analysis and exon/intron structure 7,8. The first duplication produced the primordial SUMO1/5 and SUMO2/3/4 genes. The primordial SUMO2/3/4 gene underwent one gene duplication that generated the precursor for SUMO4 and the primordial SUMO2/3 gene, and the primordial SUMO2/3 gene duplicated again to generate the precursors for the current SUMO2 and SUMO3 genes. Similarly, the primordial SUMO1/5 gene underwent one additional gene duplication that over time generated the current SUMO1 and SUMO5 genes. Each gene duplication provided some freedom from the selective constraints related to the function of the primordial copy, thus allowing the functional differentiation and divergence that resulted in the five SUMO genes presently found in the human genome. The proteins encoded by these genes exhibit very similar overall shapes, variable levels of amino acid identity, and clear functional differentiation, as recently demonstrated 9. As such, the SUMO genes and their protein products can be considered to be paralogs, as per current definition of the term 10,11. In their mature proteolyticallyprocessed form, out of the five SUMO paralogs present in humans, SUMO2 and SUMO3 exhibit the closest sequence identity, differing from each other only by three amino acid residues. SUMO1 exhibits only 49% identity with SUMO2. SUMO4 is more closely related to SUMO2/3 than to SUMO1, exhibiting 85% identity to SUMO2. Finally, SUMO5 is more closely related to SUMO1 than to SUMO2/3, displaying 88% identity with SUMO1. Importantly, SUMO1, 2, and 3 are widely expressed throughout the body, with their transcripts being easily detected in most organs and tissues 9. In contrast, SUMO4 expression is limited to kidney, immune cells, pancreas, and placenta 12,13 , and SUMO5 is limited to blood cells and testis 9,14. SUMOylation regulates every major event taking place in mammalian cells, including DNA repair 15,16 , transcription 17,18 , splicing 19 , ribosomal assembly 20 , progression through the cell cycle 21 , mitosis 22 , meiosis 23 , nucleocytoplasmic traffic 24 , signal transduction 25 , cytoskeletal and mitochondrial dynamics 26,27 , apoptosis and autophagy 28-31 , the activation of ion channels 32 , glycolysis 33,34 , and every metabolic pathway 35. In addition to its critical role as a regulator of normal cellular functions, SUMOylation also coordinates the adaptive responses required to survive most cellular stressors, including genotoxic attack 36,37 , heat-shock 38 , cold-shock 39 , oxygen and glucose deprivation 40-42 , and viral infection 43,44. Importantly, all the stresses enumerated above result in substantial increases in the overall profile of SUMO conjugation in the cell, a phenomenon best observed by immunoblot analysis. The mechanisms responsible for the global increases in cellular SUMOylation triggered by stress remain to be fully characterized. The initial reports related to an increase in cellular SUMOylation during stress indicated that only SUMO2 and SUMO3 SUMOylation were increased. However, subsequent reports by us and others indicated that, for some types of stress, the increase in cellular SUMOylation also involved SUMO1 40,45,46. As for how the increase in SUMOylation is achieved, some authors have indicated, based primarily on assessments performed using mass spectrometry data, that the increases are the result of a redistribution of SUMO from one pool of targets, including free unconjugated SUMO, to another 38,47. Such redistribution could be mediated by the activation and/or inactivation of specific sets of SUMO deconjugating enzymes and SUMO ligases. This redistribution model precludes the need for a net increase in the expression of any given SUMO paralog.

Scientific Reports