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Pleiotropic Roles of a KEAP1-Associated Deubiquitinase, OTUD1

ANTIOXIDANTS (2023)

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Article Cell Biology

The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region

Guanlan Fan et al.

Summary: In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation, and a short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. OUN-36-based therapy efficiently abrogates Akt feedback reactivation and sensitizes cancer cells to chemotherapy and immunotherapy.

CELL REPORTS (2023)

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Review Cell Biology

An expanded lexicon for the ubiquitin code

Ivan Dikic et al.

Summary: Recent studies have advanced our understanding of ubiquitylation, revealing unconventional ubiquitylation mechanisms used by pathogens to promote infection. Structural studies have shown that ubiquitin functions involve complex multivalent interactions that regulate transcription or protein degradation. Furthermore, these interactions can induce conformational changes and regulate protein degradation or transcription. These newly discovered mechanisms provide potential opportunities for innovative therapeutic interventions for diseases such as cancer and infectious diseases.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2023)

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Article Hematology

The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease

Qiao Cheng et al.

Summary: Disorders of the ubiquitin-proteasome system (UPS) have been found to affect the incidence and mortality of various diseases. This study uncovered a vital role of the deu-biquitinase OTUD1 in the regulation of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The study revealed that OTUD1 interacts with Notch2-ICD (NICD), cleaves the ubiquitin of NICD, and promotes the accumulation of NICD protein in T cells, thereby amplifying the cascade of aGVHD. Moreover, the study identified dapagliflozin as an inhibitor of the OTUD1/NICD axis that significantly prolonged the survival of aGVHD mice.

BLOOD (2023)

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Article Biochemistry & Molecular Biology

Mouse endothelial OTUD1 promotes angiotensin II-induced vascular remodeling by deubiquitinating SMAD3

Zhuqi Huang et al.

Summary: Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted the role of deubiquitinases, specifically OTUD1, in angiotensin II-induced vascular remodeling. OTUD1 deletion attenuates the pathological changes associated with vascular remodeling, while OTUD1 overexpression aggravates these changes. Mechanistically, OTUD1 deubiquitinates and stabilizes SMAD3, promoting SMAD3/SMAD4 complex formation and nuclear translocation, ultimately leading to transcriptional regulation of genes involved in vascular EndMT and remodeling. SMAD3 inhibition reverses OTUD1-promoted vascular remodeling. These findings suggest that OTUD1 could be a potential therapeutic target for diseases related to vascular remodeling.

EMBO REPORTS (2023)

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Article Immunology

The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NE-κB signaling

Bo Wu et al.

Summary: The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination play crucial roles in colonic inflammation. Ovarian tumor deubiquitinase 1 (OTUD1) inhibits RIPK1-mediated NF-kappa B activation to alleviate inflammation, with lower expression in UC patients. OTUD1 is a potential target for treating IBD due to its regulatory role in intestinal inflammation.

CELLULAR & MOLECULAR IMMUNOLOGY (2022)

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Article Biochemistry & Molecular Biology

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Wentao Liu et al.

Summary: This study investigates the clinicopathological role of the OTUD family in ccRCC and identifies that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs.

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES (2022)

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Article Endocrinology & Metabolism

Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation

Seon Min Woo et al.

Summary: The study revealed that melatonin induces apoptosis in cancer cells by stabilizing Bim through upregulating OTUD1. It demonstrated the mechanism of melatonin-induced apoptosis and the interaction between OTUD1 and Bim, providing a new target for cancer treatment.

JOURNAL OF PINEAL RESEARCH (2022)

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Article Oncology

The deubiquitinase OTUD1 inhibits non-small cell lung cancer progression by deubiquitinating and stabilizing KLF4

Xiaoyan Ma et al.

Summary: The study reveals that OTUD1 suppresses NSCLC progression by mediating KLF4 stabilization, providing a potential gene target for the treatment of NSCLC.

THORACIC CANCER (2022)

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Review Cell Biology

Deubiquitinases in Neurodegeneration

Abudu I. Bello et al.

Summary: This article provides a brief overview of the role of DUBs in neurodegeneration and their potential as therapeutic targets.

CELLS (2022)

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Review Cell Biology

MCL-1 is a clinically targetable vulnerability in breast cancer

Matthew L. Winder et al.

Summary: MCL-1, a pro-survival member of the BCL-2 family, has emerged as an attractive target in breast cancer due to its potential to restore apoptosis and enhance the efficacy of conventional therapies.

CELL CYCLE (2022)

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Review Immunology

CARD9 Signaling, Inflammation, and Diseases

Xuanyou Liu et al.

Summary: The CARD9 protein is expressed in immune cells and plays a crucial role in the function of the innate and adaptive immune systems through interactions with other signaling molecules. CARD9-mediated signaling is involved in regulating inflammatory responses and oxidative stress, and abnormalities in CARD9 and its signaling pathways are associated with various pathological conditions.

FRONTIERS IN IMMUNOLOGY (2022)

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Article Biochemistry & Molecular Biology

Deubiquitinase OTUD1 Resolves Stalled Translation on polyA and Rare Codon Rich mRNAs

Renata Snaurova et al.

Summary: OTUD1 is a deubiquitinating enzyme that plays roles in various cellular processes, including cancer and innate immune signaling pathways. This study reveals that OTUD1 is predominantly present in the translation and RNA metabolism protein complexes. It associates with ribosome subunits, elongation factors, and the E3 ubiquitin ligase ZNF598, but not with the translation initiation machinery. The catalytic activity of OTUD1 suppresses ribosome stalling triggered by polyA by inhibiting ZNF598-mediated RPS10 ubiquitination and promotes polysome formation. Gene expression analysis suggests that OTUD1 regulates the stability of mRNA with rare codon enrichment by antagonizing ZNF598.

MOLECULAR AND CELLULAR BIOLOGY (2022)

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Article Multidisciplinary Sciences

The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma

Alexander Vdovin et al.

Summary: Development of proteasome inhibitor resistance is a common problem in patients with multiple myeloma. The authors show that deubiquitinase OTUD1 protects PRDX4 from degradation, resulting in increased load of misfolded immunoglobulins and sensitizing myeloma cells for proteasome inhibition.

NATURE COMMUNICATIONS (2022)

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Article Cardiac & Cardiovascular Systems

Molecular Mechanism of Sevoflurane Preconditioning Based on Whole-transcriptome Sequencing of Lipopolysaccharide-induced Cardiac Dysfunction in Mice

Jiawei Xie et al.

Summary: Sevoflurane has been shown to be cardioprotective in septic mice by regulating the mitogen-activated protein kinase signaling pathway and a lncRNA-miRNA-mRNA network. This study identified 11 potential essential genes and provided a novel mechanism of sevoflurane-induced cardioprotection.

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY (2022)

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Article Cell Biology

OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

Daisuke Oikawa et al.

Summary: This study investigates the effects of DUBs on NF-Kappa B activation and identifies OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-Kappa B pathway, apoptosis, and the interferon antiviral pathway. It is also involved in the KEAP1-mediated antioxidant response and cell death pathways.

CELL DEATH & DISEASE (2022)

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Article Biochemistry & Molecular Biology

Ubiquitination of phosphatidylethanolamine in organellar membranes

Jun-ichi Sakamaki et al.

Summary: This study reveals that ubiquitin family proteins can conjugate to phospholipids, not only ATG8. This conjugation mainly occurs in endosomes and vacuoles and increases during starvation. In vitro experiments also demonstrate that liposomes containing ubiquitin-phospholipid can recruit specific protein components.

MOLECULAR CELL (2022)

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Article Multidisciplinary Sciences

A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation

Momoko Narita et al.

Summary: The authors discovered that collided ribosomes play a crucial role in quality control mechanisms. By ubiquitination, the collided ribosomes are marked and the quality control complex is recruited for subunit dissociation. The ubiquitination activity and K63-linked polyubiquitination of uS10 are critical for ribosome dissociation.

NATURE COMMUNICATIONS (2022)

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Article Immunology

Differences of macrophages in the tumor microenvironment as an underlying key factor in glioma patients

Yangyang Wang et al.

Summary: This study identified quantitative and functional differences in macrophage clusters between different grades of glioma, developed a predictive risk model, and confirmed the essential role of these genes in glioma prognosis and the immune microenvironment.

FRONTIERS IN IMMUNOLOGY (2022)

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Review Biochemistry & Molecular Biology

Non-lysine ubiquitylation: Doing things differently

Ian R. R. Kelsall

Summary: The post-translational modification of proteins with ubiquitin, which is not limited to lysine residues, but can also occur on cysteine, serine, and threonine residues, as well as the N-terminal amino group of proteins, plays a central role in various aspects of eukaryotic biology. Recent discoveries have expanded the scope of ubiquitylation to include non-proteinaceous substrates like intracellular lipids and sugars. Bacterial studies have also revealed novel pathways for ubiquitylation (and deubiquitylation) without involving the canonical enzymatic components. This review focuses on recent findings and speculates on the molecular mechanisms and physiological importance of non-lysine ubiquitylation.

FRONTIERS IN MOLECULAR BIOSCIENCES (2022)

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Article Cell Biology

Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1

Huafeng Liu et al.

Summary: This study reveals the mechanism of action of deubiquitylase OTUD1 in suppressing chemoresistance in non-small cell lung cancer (NSCLC). The results show that upregulation of OTUD1 increases the sensitivity of NSCLC cells to erlotinib by inhibiting the nuclear translocation of YAP1 and inactivating its downstream signals SOX9/SPP1.

CELL DEATH DISCOVERY (2022)

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Article Cell Biology

Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis

Hong-Guang Zhang et al.

Summary: Depression affects antiviral innate immune signaling, leading to attenuated immune response. Depression-related arginine vasopressin induces reduction of AHI1 in macrophages. Meptazinol effectively enhances antiviral defense in depression model mice.

CELL RESEARCH (2022)

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Article Biochemistry & Molecular Biology

The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity

Jia Song et al.

Summary: This study identifies OTDU1 as a crucial regulator in iron transportation in cancer, promoting the immune response against tumors. OTUD1 depletion limits tumor-reactive T-cell accumulation and exacerbates cancer progression. The data highlights the significance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.

EMBO REPORTS (2021)

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Article Virology

DDIT3 Targets Innate Immunity via the DDIT3-OTUD1-MAVS Pathway To Promote Bovine Viral Diarrhea Virus Replication

Song Wang et al.

Summary: DDIT3 inhibits the antiviral immune response by promoting MAVS degradation, leading to increased replication of BVDV. Knocking out DDIT3 enhances the antiviral innate immune response and reduces viral replication. These findings provide insights into the molecular mechanisms by which DDIT3 regulates IFN-I production.

JOURNAL OF VIROLOGY (2021)

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Article Biochemistry & Molecular Biology

Post-translational down-regulation of Nrf2 and YAP proteins, by targeting deubiquitinases, reduces growth and chemoresistance in pancreatic cancer cells

Margherita Grattarola et al.

Summary: Intrinsic chemoresistance in pancreatic ductal adenocarcinoma is associated with high levels of antioxidants, upregulated Nrf2 and YAP protein expressions. Inhibiting these proteins could potentially overcome chemoresistance in PDAC.

FREE RADICAL BIOLOGY AND MEDICINE (2021)

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Article Multidisciplinary Sciences

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

Virginia De Cesare et al.

Summary: The study focuses on exploring the esterase and isopeptidase activity of DUBs, revealing that most DUBs exhibit dual selectivity, with the ovarian tumor domain DUB class demonstrating specific isopeptidase activity and the Machado-Joseph disease (MJD) class showing highly specific ubiquitin esterase activity.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

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Article Agriculture, Dairy & Animal Science

Woody breast myopathy broiler show age-dependent adaptive differential gene expression in Pectoralis major and altered in-vivo triglyceride kinetics in adipogenic tissues

Pramir Maharjan et al.

Summary: The study revealed the gene expression differences related to muscle protein degradation, muscle fiber regeneration, and nutrient-deficient state in woody breast myopathy affected broilers. Furthermore, it showed a decrease in triglyceride synthesis in the liver of myopathy broilers, indicating potential adaptive physiological processes in response to adverse cellular conditions.

POULTRY SCIENCE (2021)

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Article Chemistry, Multidisciplinary

OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation

Qingyu Luo et al.

Summary: The study reveals the central role of OTUD1 in activating both caspase-independent and caspase-dependent apoptotic signaling by deubiquitinating AIF at specific sites, disrupting mitochondrial structure and enhancing DNA-binding ability.

ADVANCED SCIENCE (2021)

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Article Biochemistry & Molecular Biology

Characterization of Biological Pathways Regulating Acute Cold Resistance of Zebrafish

Jing Ren et al.

Summary: Research on zebrafish exposed to lethal cold stress has shown that survival pathways, including autophagy, FoxO, and MAPK signaling, enhance cold resistance, while apoptosis and necroptosis pathways lead to cold-induced mortality. Molecular markers and biological pathways associated with cold-induced damages have been identified, shedding new light on the molecular mechanisms underlying cold resistance in fish.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Immunology

OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9

Xiaorong Chen et al.

Summary: This study identifies ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9, which can activate the canonical NF-kappa B and MAPK pathway by deubiquitinating CARD9, impacting immune response following fungal stimulation.

JOURNAL OF IMMUNOLOGY (2021)

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Article Agriculture, Dairy & Animal Science

Flash dietary methionine supply over growth requirements in pigs: Multi-facetted effects on skeletal muscle metabolism

F. Gondret et al.

Summary: The study investigates the effects of dietary methionine supplementation beyond nutritional requirements in pigs on muscle amino acid profile, redox capacities, protein breakdown, and energy metabolism pathways. Subtle modifications in gene expression were found to have cumulative effects on meat quality traits, showing benefits from the supplementation.

ANIMAL (2021)

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Review Biochemistry & Molecular Biology

Expanding Role of Ubiquitin in Translational Control

Shannon E. Dougherty et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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Article Immunology

OTUD1 Negatively Regulates Type I IFN Induction by Disrupting Noncanonical Ubiquitination of IRF3

Zeming Zhang et al.

JOURNAL OF IMMUNOLOGY (2020)

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Article Biology

Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized

Danielle M. Garshott et al.

ELIFE (2020)

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The function and regulation of OTU deubiquitinases

Jiansen Du et al.

FRONTIERS OF MEDICINE (2020)

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Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

Daisuke Oikawa et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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A Human DUB Protein Array for Clarification of Linkage Specificity of Polyubiquitin Chain and Application to Evaluation of Its Inhibitors

Hirotaka Takahashi et al.

BIOMEDICINES (2020)

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Basics and principles of cellular and systemic iron homeostasis

Angeliki Katsarou et al.

MOLECULAR ASPECTS OF MEDICINE (2020)

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FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane

Derek F. Ceccarelli et al.

STRUCTURE (2019)

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The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein

Lanqin Wu et al.

CANCER CELL INTERNATIONAL (2019)

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Kirby N. Swatek et al.

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Effects of long-term feeding of rapeseed meal on skeletal muscle transcriptome, production efficiency and meat quality traits in Norwegian Landrace growing-finishing pigs

Adrijana Skugor et al.

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Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

Fatima Qadir et al.

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ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability

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MOLECULAR CELL (2018)

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Induction of OTUD1 by RNA viruses potently inhibits innate immune responses by promoting degradation of the MAVS/TRAF3/TRAF6 signalosome

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Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders

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JOURNAL OF AUTOIMMUNITY (2018)

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Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7

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