Two isoforms of otubain 1 regulate T cell anergy via GRAIL

Soares, Luis; Seroogy, Christine M.; Skrenta, Heidi; Anandasabapathy, Niroshana; Lovelace, Patricia; Chung, Chan D.; Engleman, Edgar G.; Fathman, C. Garrison

doi:10.1038/ni1017

Cited by 154 publications

(169 citation statements)

References 24 publications

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“…UBPY also binds to several other proteins: CDC25 Mm , a GDP/GTP exchange factor for Ras (Gnesutta et al, 2001); GRAIL, an E3 Ub ligase involved in anergy induction in CD4 ϩ T-cells (Soares et al, 2004); and Nrdp1, another E3 ligase that regulates the steady-state level of ErbB3 and ErbB4 RTKs (Wu et al, 2004). UBPY is implicated in deubiquitinating and regulating the stability of these proteins (Gnesutta et al, 2001;Soares et al, 2004;Wu et al, 2004).…”

Section: Ubpy Is a Deubiquitinating Enzyme For Activated Egfrmentioning

confidence: 99%

“…UBPY is implicated in deubiquitinating and regulating the stability of these proteins (Gnesutta et al, 2001;Soares et al, 2004;Wu et al, 2004). Therefore, through its deubiquitinating activity, UBPY probably participates in several different cellular processes by regulating the degradation or stability of distinct substrate proteins.…”

Section: Ubpy Is a Deubiquitinating Enzyme For Activated Egfrmentioning

confidence: 99%

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Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

250

264

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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Section: Ubpy Is a Deubiquitinating Enzyme For Activated Egfrmentioning

confidence: 99%

Section: Ubpy Is a Deubiquitinating Enzyme For Activated Egfrmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

250

264

View full text Add to dashboard Cite

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“…Since OTUB1‐isoform2 exists as a ncRNA in somatic organs except in the lymphatic tissues (https://www.ncbi.nlm.nih.gov/nuccore/NR_003089.1)%5b20 20, and our previous study has also confirmed its existence as a ncRNA in gastric cancer,27 we first determined the level of OTUB1‐isoform2 mRNA using RT‐qPCR with the specific primers. The RT‐qPCR assay was performed in paired tumour and paratumorous tissues from 114 patients with ovarian cancer (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…OTU domain‐containing ubiquitin aldehyde binding 1 (OTUB1) is a member of the OTU (ovarian tumour) superfamily and has two isoforms 20. The predominantly expressed isoform1 encodes the OTUB1 protein, which functions as a deubiquitinase 21, 22.…”

Section: Introductionmentioning

confidence: 99%

The non‐coding RNA OTUB1‐isoform2 promotes ovarian tumour progression and predicts poor prognosis

Wang

Ning

Wei

et al. 2018

J Cellular Molecular Medi

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Ovarian cancer is the leading malignancy of the female reproductive system and is associated with inconspicuous early invasion and metastasis. We have previously reported that the oncogene OTUB1 plays a crucial role in ovarian cancer progression, but the role of its isoform, the non‐coding RNA OTUB1‐isoform2, in ovarian cancer is still elusive. Here, we reported that OTUB1‐isoform2 expression in ovarian cancer tissues was significantly higher than that in the paired paratumorous tissues (P < .01). The patients with high expression of OTUB1‐isoform2 had larger tumours than those with low expression (P < .05). The high expression of OTUB1‐isoform2 was correlated with the involvement of bilateral ovaries (P < .05), lymph node metastasis (P < .05), vascular invasion (P < .05), greater omentum involvement (P < .01), fallopian tube involvement (P < .05), advanced FIGO stages (P < .01) and recurrence (P < .01). Moreover, OTUB1‐isoform2 served as an independent negative prognostic predictor for disease‐free survival (DFS) and disease‐specific survival (DSS). Overexpression of OTUB1‐isoform2 in the ovarian cancer cells stimulated cell proliferation, migration and invasion both in vitro and in vivo. In summary, our study suggested that OTUB1‐isoform2 is a novel prognostic biomarker with independent oncogenic functions for ovarian cancer.

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“…Among the bestcharacterized putative DUB involved in E3 ligases signaling are Otubain-1 and FAM/USP9X, which regulate Grail and Itch autoubiquitylation, respectively. While FAM-dependent deubiquitylation protects Itch from auto-ubiquitylation-driven degradation, Otubai-1 deubiquitylation of Grail results in its proteolysis [78,79]. Otubain-1 modulation of Grail has been suggested to contribute to the regulation of T-cell anergy and, as recently proposed, may participate in T-cell activation and T-cell proliferation [78,80].…”

Section: Reversing Anergy: Deubiquitylation and Il-2 Signalsmentioning

confidence: 97%

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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Two isoforms of otubain 1 regulate T cell anergy via GRAIL

Cited by 154 publications

References 24 publications

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

The non‐coding RNA OTUB1‐isoform2 promotes ovarian tumour progression and predicts poor prognosis

E3 ubiquitin ligases in T‐cell tolerance

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