Sumoylation regulates ER stress response by modulating calreticulin gene expression in XBP-1-dependent mode in Caenorhabditis elegans

Lim, Young‐Hun; Lee, Dukgyu; Kalichamy, Karunambigai; Hong, Su Young; Michalak, Marek; Ahnn, Joohong; Kim, Do Han; Lee, Sun-Kyung

doi:10.1016/j.biocel.2014.06.005

Cited by 26 publications

(29 citation statements)

References 38 publications

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“…57 Decreased levels of UBC9 also lead to accumulation of aggregated proteins and changes in cell metabolism. 58 Our data show that cardiac specific expression of UBC9 protein results in increased SUMOylation levels that are accompanied by increased basal autophagic flux. CM-specific UBC9 protein expression significantly increased the expression of multiple transcripts encoding autophagy proteins as well.…”

Section: Discussionmentioning

confidence: 60%

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Gupta

McLendon

Gulick

et al. 2016

Circulation Research

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Rationale SUMOylation plays an important role in cardiac function and can be protective against cardiac stress. Recent studies show that SUMOylation is an integral part of the ubiquitin proteasome system (UPS) and expression of the SUMO E2 enzyme UBC9 improves cardiac protein quality control. However, the precise role of SUMOylation on other protein degradation pathways, particularly autophagy, remains undefined in the heart. Objective To determine whether SUMOylation affects cardiac autophagy and whether this effect is protective in a mouse model of proteotoxic cardiac stress. Methods and Results We modulated expression of UBC9, a SUMO E2 ligase, using gain- and loss-of-function in neonatal rat ventricular cardiomyocytes (NRVC). UBC9 expression appeared to directly alter autophagic flux. To confirm this effect in vivo, we generated transgenic mice overexpressing UBC9 in cardiomyocytes (CM). These mice have an increased level of SUMOylation at baseline and, in confirmation of the data obtained from NRVCs, demonstrated increased autophagy, suggesting that increased UBC9-mediated SUMOylation is sufficient to upregulate cardiac autophagy. Finally, we tested the protective role of SUMOylation-mediated autophagy by expressing UBC9 in a model of cardiac proteotoxicity, induced by CM-specific expression of a mutant αB crystallin, CryABR120G, which shows impaired autophagy. UBC9 overexpression reduced aggregate formation, decreased fibrosis, reduced hypertrophy and improved cardiac function and survival. Conclusions The data show that increased UBC9-mediated SUMOylation is sufficient to induce relatively high levels of autophagy and may represent a novel strategy for increasing autophagic flux and ameliorating morbidity in proteotoxic cardiac disease.

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Section: Discussionmentioning

confidence: 60%

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Gupta

McLendon

Gulick

et al. 2016

Circulation Research

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“…Scellnetor uncovered that CALR is highly expressed in the neutrophil trajectory compared to the erythrocyte trajectory. CALR code for a multifunctional protein called calreticulin, which counteracts ER stress and is involved in correct maintenance of calcium ions in the ER [36][37][38][39][40] . The gene P4HB (Fig 2e) have also been found to downregulate ER stress 41 .…”

Section: Gene Set Enrichment Analysis Resultsmentioning

confidence: 99%

Comparative single-cell trajectory network enrichment identifies pseudo-temporal systems biology patterns in hematopoiesis and CD8 T-cell development

Agb

Oubounyt

Kanev

et al. 2020

Preprint

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Single cell transcriptomics (scRNA-seq) technologies allow for investigating cellular processes on an unprecedented resolution. While software packages for scRNA-seq raw data analysis exist, no method for the extraction of systems biology signatures that drive different pseudo-time trajectories exists.Hence, pseudo-temporal molecular sub-network expression profiles remain undetermined, thus, hampering our understanding of the molecular control of cellular development on a single cell resolution. We have developed Scellnetor, the first network-constraint time-series clustering algorithm implemented as interactive webtool to identify modules of genes connected in a molecular interaction network that show differentiating temporal expression patterns. Scellnetor allows selecting two differentiation courses or two developmental trajectories for comparison on a systems biology level.Scellnetor identifies mechanisms driving hematopoiesis in mouse and mechanistically interpretable subnetworks driving dysfunctional CD8 T-cell development in chronic infections. Scellnetor is the first method to allow for single cell trajectory network enrichment for systems level hypotheses generation, thus lifting scRNA-seq data analysis to a systems biology level. It is available as an interactive online tool at https://exbio.wzw.tum.de/scellnetor/. Introduction Single-cell RNA sequencing (scRNA-seq) allows researchers to perform cellular developmental studies with a hitherto unseen fine granularity. Single-cell transcriptomes have paved the way for novel discoveries in various biomedical fields by improving the understanding of how transcriptional profiles relate to cell phenotypes. A range of algorithms have been invented for clustering of scRNA-seq data and for inferring differentiation trajectories 1-3 . Clustering assumes that single cells can be divided into distinct groups whereas trajectory inference aims to arrange cells such that continuous phenotypes can be traced on a low dimensional cell map 4 . Important examples of the latter include diffusion maps 5,6 and pseudotemporal ordering of single cells 3,7 . Both algorithms seek to position single cells such that their coordinates reflect their developmental statuses in relation to the other cells. Additionally, several software packages have been developed for the entire analysis pipeline, from pre-processing to clustering and identification of differentially expressed genes. Scanpy 8 , Seurat 9 and SINCERA 10 are examples of such software packages. Though scRNA-seq data is still challenged by noise 11 , combinations of different tools and algorithms have helped to unravel hidden inter-cellular mechanisms and shed light on unknown cellular paths of differentiation and disease progression 12-14 .Typical computational analyses of single cell gene expression data involve a pre-processing step, where, e.g., cells with high levels of mitochondrial DNA and few expressed genes are removed 2,15-18 . This is followed by a clustering of single-cells' transcriptional profiles and/or infere...

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“…Soluble IFB-1 could be detected in WT embryos at early elongation while in smo-1(RNAi) embryos abnormal thick and short filaments were accumulated (Kaminsky et al). Another study showed that knockdown of ubc-9 gave the same abnormal IF assembly phenotypes in embryos (Lim et al, 2014). It is possible that in addition to SUMO function as a sequestering factor, sumoylated IFB-1 binds accessory, regulatory and polymerization factors that are required for normal filament assembly.…”

Section: Intermediate Filament Assemblymentioning

confidence: 99%

“…A few more examples of identified SUMO targets in C. elegans are the ER stress responsive transcription factor XBP-1 (Lim et al, 2014), the nuclear AAA ATPase FIGL-1/Fidgetin (Onitake et al, 2012) and BRD-1, the ortholog of BARD1 (BRCA1-associated RING domain 1) (Boulton et al, 2004). As detailed above, many targets of SUMO were identified using the Y2H system.…”

Section: Additional Substrates For Sumo and Possible Cross Talk With mentioning

confidence: 99%

The SUMO system in Caenorhabditis elegans development

Broday¹

2017

Int. J. Dev. Biol.

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SUMO, a small ubiquitin-like modifier, is a highly conserved post translational modification and a central regulatory system in eukaryotes. Sumoylation modulates the activities of multiple proteins, mainly in the nucleus, such as transcription factors, chromatin modifiers, and proteins involved in DNA replication and repair. However, SUMO also modifies substrates in the cytoplasm, mitochondria, plasma and ER membrane. This review summarizes our current knowledge on the functions of sumoylation in C. elegans development. SUMO modification is highly reversible and several examples described here establish its function as a molecular switch during embryogenesis and postembryonic organogenesis.

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Sumoylation regulates ER stress response by modulating calreticulin gene expression in XBP-1-dependent mode in Caenorhabditis elegans

Cited by 26 publications

References 38 publications

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Comparative single-cell trajectory network enrichment identifies pseudo-temporal systems biology patterns in hematopoiesis and CD8 T-cell development

The SUMO system in Caenorhabditis elegans development

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