The Ubiquitin-fold Modifier 1 (Ufm1) Cascade of Caenorhabditis elegans

Hertel, Patrick; Daniel, Jens; Stegehake, Dirk; Vaupel, Hannah; Kailayangiri, Sareetha; Gruel, Clio; Woltersdorf, Christian; Liebau, Eva

doi:10.1074/jbc.m113.458000

Cited by 28 publications

(30 citation statements)

References 44 publications

(74 reference statements)

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“…These proteins regulate cytokine production (Th2/ IL4), inflammatory signaling through the NFκB pathway, activate innate immune responses against bacterial infection, activate apoptosis, activate T cells, play an important role in unfolded protein response pathway/ ER stress response pathway and activate the complement cascade (Cannons et al 2011; Hayashi et al 2001; Hertel et al 2013; Komatsu et al 2004; Ma and Deenick 2011; Means et al 2003; Schwartzberg et al 2009; Tordella et al 2013; Wilson et al 2013). All of these transcripts may play a role in p53-mediated inflammation during aging and AMD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

2015

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The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53, known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset (www.genenetwork.org) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology based approach. We identified a significant trans-QTL on chromosome 1 (region 172–177Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc-receptors, interferon-inducible family genes and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.

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Section: Discussionmentioning

confidence: 99%

Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

2015

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“…UBA-5 was cloned and expressed as published by our group [67]. Further controls were performed with the bacterial cell wall components LPS (1 μ g/mL; Sigma-Aldrich, Taufkirchen, Germany) and lipoteichoic acid (LTA, 0.1 μ g/mL; Sigma-Aldrich, Taufkirchen) to analyze potential endotoxin contaminations and to compare both responses.…”

Section: Methodsmentioning

confidence: 99%

Multifunctional Thioredoxin-Like Protein from the Gastrointestinal Parasitic NematodesStrongyloides rattiandTrichuris suisAffects Mucosal Homeostasis

Ditgen

Anandarajah

Hansmann

et al. 2016

Journal of Parasitology Research

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The cellular redox state is important for the regulation of multiple functions and is essential for the maintenance of cellular homeostasis and antioxidant defense. In the excretory/secretory (E/S) products of Strongyloides ratti and Trichuris suis sequences for thioredoxin (Trx) and Trx-like protein (Trx-lp) were identified. To characterize the antioxidant Trx-lp and its interaction with the parasite's mucosal habitat, S. ratti and T. suis Trx-lps were cloned and recombinantly expressed. The primary antioxidative activity was assured by reduction of insulin and IgM. Further analysis applying an in vitro mucosal 3D-cell culture model revealed that the secreted Trx-lps were able to bind to monocytic and intestinal epithelial cells and induce the time-dependent release of cytokines such as TNF-α, IL-22, and TSLP. In addition, the redox proteins also possessed chemotactic activity for monocytic THP-1 cells and fostered epithelial wound healing activity. These results confirm that the parasite-secreted Trx-lps are multifunctional proteins that can affect the host intestinal mucosa.

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“…Suppression of the Ufm1 pathway components by siRNA led to morphological changes of the ER network in U2OS cells (21). The Uba5-Ufm1 conjugation pathway was also shown to be implicated in the ER stress response in Caenorhabditis elegans (22). All these studies suggest that protein ufmylation is an important pathway that cells have evolved to maintain proper function of the ER and to mediate ER stress responses.…”

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confidence: 86%

Mechanistic Study of Uba5 Enzyme and the Ufm1 Conjugation Pathway

Gavin

Hoar

et al. 2014

Journal of Biological Chemistry

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Background: Human ubiquitin-like protein Ufm1 and its activating enzyme, Uba5, are involved in endoplasmic reticulum (ER) stress response. Results: The Uba5-Ufm1 conjugation pathway is characterized in both reconstituted systems and cellular settings. Conclusion: Uba5 activates Ufm1 via a distinct two-step mechanism. Significance: This study represents the first mechanistic characterization of Uba5, a homodimeric member of the E1 enzyme family.

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The Ubiquitin-fold Modifier 1 (Ufm1) Cascade of Caenorhabditis elegans

Cited by 28 publications

References 44 publications

Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

Multifunctional Thioredoxin-Like Protein from the Gastrointestinal Parasitic NematodesStrongyloides rattiandTrichuris suisAffects Mucosal Homeostasis

Mechanistic Study of Uba5 Enzyme and the Ufm1 Conjugation Pathway

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