The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense

Basler, Michael; Buerger, Stefanie; Groettrup, Marcus

doi:10.1016/j.molimm.2015.04.012

Cited by 30 publications

(29 citation statements)

References 26 publications

(39 reference statements)

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“…We believe it is unlikely, however, that inhibition of FAT10ylation makes a major contribution to our findings because UBA6 is present at ~10% of the levels of UBA1 in most cells (8) and the evidence to date does not support a major role for FAT10 in antigen presentation (47). …”

Section: Discussionmentioning

confidence: 69%

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

Wei

Zanker

Carluccio

et al. 2017

The Journal of Immunology

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CD8+ T cell immunosurveillance is based on recognizing oligopeptides presented by MHC class I molecules. Despite decades of study, the importance of protein ubiquitylation to peptide generation remains uncertain. Here, we examine the ability of MLN7243, a recently described ubiquitin activating enzyme E1-inhibitor, to block overall cytosolic peptide generation and generation of specific peptides from vaccinia- and influenza A virus-encoded proteins. We show that MLN7243 rapidly inhibits ubiquitylation in a variety of cell lines, and can profoundly reduce generation of cytosolic peptides. Kinetic analysis of specific peptide generation reveals that ubiquitylation of defective ribosomal products (DRiPs) is rate limiting in generating class I peptide complexes. More generally, our findings demonstrate that the requirement for ubiquitylation in MHC class I restricted antigen processing varies with class I allomorph, cell type, source protein, and peptide context. Thus, both ubiquitin-dependent and independent pathways robustly contribute to MHC class I based immunosurveillance.

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Section: Discussionmentioning

confidence: 69%

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

Wei

Zanker

Carluccio

et al. 2017

The Journal of Immunology

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“…Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control.…”

Section: Sumo: a Ubiquitin-like Modifier That Regulates Nuclear Procementioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

238

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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“…Here we show that variation at the UBD locus (also called FAT10) is a genetic modifier of the risk of FSGS in individuals with a high-risk APOL1 genotype. UBD encodes a ubiquitin-like protein modifier that targets proteins to the 26S proteasome for degradation (6,7). Like APOL1, UBD is up-regulated in response to proinflammatory stimuli including IFN-γ (8).…”

mentioning

confidence: 99%

UBD modifies APOL1 -induced kidney disease risk

Zhang

Wang

Tian

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with We performed an admixture mapping study to identify genetic modifiers of-associated kidney disease. Individuals with two risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the locus correlates with lower levels of expression. In cell-based experiments, the disease-associated alleles (known as G1 and G2) lead to increased abundance of mRNA but to decreased levels of protein. gene expression inversely correlates with G1 and G2 -mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both and , which interact in a functionally important manner. UBD appears to mitigate-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in and expression appear to modify the -associated kidney phenotype.

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The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense

Cited by 30 publications

References 26 publications

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

UBD modifies APOL1 -induced kidney disease risk

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