4.7 Review

Advances in the Study of the Ubiquitin-Editing Enzyme A20

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Article Gastroenterology & Hepatology

ABIN3 Negatively Regulates Necroptosis-induced Intestinal Inflammation Through Recruiting A20 and Restricting the Ubiquitination of RIPK3 in Inflammatory Bowel Disease

Mingxia Zhou et al.

Summary: This study found that excessive necroptosis plays an important role in uncontrolled inflammation and intestinal barrier defects in IBD and experimental colitis. ABIN3 regulates inflammatory response and intestinal barrier function by interacting with A20 and coordinating the K63 deubiquitination modification of necroptosis.

JOURNAL OF CROHNS & COLITIS (2021)

Article Hematology

MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis

Xinfang Yu et al.

Summary: MYD88(L265P) mutation leads to enhanced NF-κB activation through K63-linked nonproteolytic polyubiquitination catalyzed by RNF138, while A20 mediates proteasomal degradation of RNF138 to suppress NF-κB activation. This mutation-specific biochemical reaction plays a critical role in B-cell oncogenesis, providing a potential therapeutic target for MYD88(L265P) without affecting MYD88(WT) critical for innate immunity.
Article Clinical Neurology

Overexpression of the ubiquitin-editing enzyme A20 in the brain lesions of Multiple Sclerosis patients: moving from systemic to central nervous system inflammation

Simona Perga et al.

Summary: Recent evidence suggests that A20, an anti-inflammatory enzyme, is highly expressed in brain tissues of MS patients, especially in active lesions, indicating its crucial role in chronic inflammation in multiple sclerosis pathology.

BRAIN PATHOLOGY (2021)

Article Endocrinology & Metabolism

MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating A20

X. Ding et al.

Summary: The study found that miR-21-5p in macrophage-derived EVs regulates podocyte injury in DN by interacting with A20. Inhibiting miR-21-5p in EVs can reduce podocyte injury, indicating the potential therapeutic target for DN.

JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION (2021)

Review Biochemistry & Molecular Biology

Beyond K48 and K63: non-canonical protein ubiquitination

Michal Tracz et al.

Summary: Protein ubiquitination, initially known for its role in proteolysis, is now recognized as essential for various cellular processes. Different types of ubiquitin linkages, beyond the commonly studied K48- and K63-linked chains, are equally important and are receiving increasing attention in recent research.

CELLULAR & MOLECULAR BIOLOGY LETTERS (2021)

Article Cell Biology

CHRFAM7A Overexpression Attenuates Cerebral Ischemia-Reperfusion Injury via Inhibiting Microglia Pyroptosis Mediated by the NLRP3/Caspase-1 pathway

Xiangyuan Cao et al.

Summary: The study found that overexpression of CHRFAM7A attenuated cerebral ischemia-reperfusion injury by inhibiting microglia pyroptosis through the NLRP3/Caspase-1 pathway and promoting microglia polarization to the M2 phenotype.

INFLAMMATION (2021)

Article Biochemistry & Molecular Biology

Interaction of RIPK1 and A20 modulates MAPK signaling in murine acetaminophen toxicity

Andrea Iorga et al.

Summary: The kinase-independent platform function of RIPK1 is involved in APAP toxicity. Adult RIPK1(HepCKO) mice are protected against APAP by upregulating A20 and attenuating JNK signaling through ASK1, conversely, A20(HepCKO) worsens injury from APAP.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

Article Immunology

Bavachin exerted anti-neuroinflammatory effects by regulation of A20 ubiquitin-editing complex

Yayun Wang et al.

Summary: Bavachin exerts anti-neuroinflammatory effects by inhibiting NF-KB signaling and regulating the ubiquitin-editing enzyme A20 complex, which has important clinical significance for the potential treatment of neurological disorders.

INTERNATIONAL IMMUNOPHARMACOLOGY (2021)

Article Plant Sciences

Formononetin attenuates atopic dermatitis by upregulating A20 expression via activation of G protein-coupled estrogen receptor

Weiyuan Yuan et al.

Summary: The study showed that FMN attenuates AD by upregulating A20 expression via activation of GPER. This new strategy may have effective therapeutic potential for AD and other inflammatory disorders.

JOURNAL OF ETHNOPHARMACOLOGY (2021)

Article Multidisciplinary Sciences

E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

Peng Gao et al.

Summary: The study highlights the crucial role of Nedd4l in regulating antiviral immunity through promoting ubiquitination of TRAF3, and disruption of Nedd4l impairs the antiviral immune response both in vitro and in vivo.

NATURE COMMUNICATIONS (2021)

Article Immunology

NOD1 Agonist Protects Against Lipopolysaccharide and D-Galactosamine-Induced Fatal Hepatitis Through the Upregulation of A20 Expression in Hepatocytes

Fang Jia et al.

Summary: The study showed that pretreatment with NOD1 agonist can significantly reduce mortality, ALT levels, and hepatocyte apoptosis induced by LPS/D-GalN, independent of TNF-alpha inhibition. NOD1 agonist pretreatment also attenuated TNF-alpha/D-GalN-induced apoptotic liver damage.

FRONTIERS IN IMMUNOLOGY (2021)

Article Cardiac & Cardiovascular Systems

Histone Methyltransferase Dot1L Contributes to RIPK1 Kinase-Dependent Apoptosis in Cerebral Ischemia/Reperfusion

Jinghuan Wang et al.

Summary: Inhibiting Dot1L can reverse ischemia-induced neuronal apoptosis and alleviate injury in neurons treated with oxygen-glucose deprivation followed by reoxygenation, ultimately reducing brain damage caused by middle cerebral artery occlusion. This highlights the potential therapeutic strategy of targeting Dot1L in ischemic stroke.

JOURNAL OF THE AMERICAN HEART ASSOCIATION (2021)

Article Cell Biology

Giardia duodenalis and Its Secreted PPIB Trigger Inflammasome Activation and Pyroptosis in Macrophages through TLR4-Induced ROS Signaling and A20-Mediated NLRP3 Deubiquitination

Lin Liu et al.

Summary: This study found that infection with Giardia duodenalis can activate pyroptosis in macrophages, with NLRP3 inflammasome playing a crucial role in this process. The effectiveness of A20 as a regulatory factor was confirmed, and a correlation was observed between TLR4, ROS enhancement, and pyroptotic signaling. Through secretome analysis, several Giardia-secreted proteins were identified as trigger factors for pyroptosis in macrophages.
Article Cardiac & Cardiovascular Systems

A20/TNFAIP3 Increases ENOS Expression in an ERK5/KLF2-Dependent Manner to Support Endothelial Cell Health in the Face of Inflammation

Cleide Angolano et al.

Summary: This study found that overexpression of A20 in endothelial cells can increase eNOS transcription in an ERK5/KLF2-dependent manner and promote eNOS activating phosphorylation, preventing eNOS downregulation by TNF. This novel function of A20 further qualifies its therapeutic promise in preventing/treating atherosclerosis.

FRONTIERS IN CARDIOVASCULAR MEDICINE (2021)

Article Biochemistry & Molecular Biology

MiR-342 controls Mycobacterium tuberculosis susceptibility by modulating inflammation and cell death

Beibei Fu et al.

Summary: The research reveals that the miR-342-3p/SOCS6 axis plays a crucial role in regulating anti-Mtb immunity and the balance between cell apoptosis and necrosis during Mtb infection, providing new insights for developing host-directed therapies targeting these pathways.

EMBO REPORTS (2021)

Article Multidisciplinary Sciences

NEK1-mediated retromer trafficking promotes blood-brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Huibing Wang et al.

Summary: Mutations in the NEK1 gene disrupt retromer-mediated trafficking, leading to RIPK1 activation and neuroinflammation. Dietary intervention targeting metabolism may provide a therapeutic strategy for NEK1-related disorders.

NATURE COMMUNICATIONS (2021)

Article Cell Biology

A20 at the Crossroads of Cell Death, Inflammation, and Autoimmunity

Arne Martens et al.

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2020)

Review Biochemistry & Molecular Biology

Control of the inflammasome by the ubiquitin system

Gloria Lopez-Castejon

FEBS JOURNAL (2020)

Letter Dermatology

A20 down-regulation promotes UVB-induced inflammation via activation of the NF-κB pathway

Yan Chen et al.

JOURNAL OF DERMATOLOGICAL SCIENCE (2020)

Article Cell Biology

Microglial A20 Protects the Brain from CD8 T-Cell-Mediated Immunopathology

Alma Nazlie Mohebiany et al.

CELL REPORTS (2020)

Review Immunology

A20 and Cell Death-driven Inflammation

Dario Priem et al.

TRENDS IN IMMUNOLOGY (2020)

Editorial Material Immunology

A20 restricts inflammation via ubiquitin binding

Shao-Cong Sun

NATURE IMMUNOLOGY (2020)

Review Biochemistry & Molecular Biology

Transcriptional Regulation of Inflammasomes

Maxence Cornut et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

Review Cell Biology

A20: A multifunctional tool for regulating immunity and preventing disease

Barbara A. Malynn et al.

CELLULAR IMMUNOLOGY (2019)

Article Multidisciplinary Sciences

Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis

Karolina Slowicka et al.

NATURE COMMUNICATIONS (2019)

Review Cell Biology

Branching Out: Improved Signaling by Heterotypic Ubiquitin Chains

Diane L. Haakonsen et al.

TRENDS IN CELL BIOLOGY (2019)

Review Physiology

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

G. Momtazi et al.

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY (2019)

Article Cell Biology

miR-200a enhances TRAIL-induced apoptosis in gastric cancer cells by targeting A20

Tianshu Guo et al.

CELL BIOLOGY INTERNATIONAL (2018)

Review Cell Biology

Mechanism and medical implications of mammalian autophagy

Ivan Dikic et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2018)

Article Multidisciplinary Sciences

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation

Sofie Voet et al.

NATURE COMMUNICATIONS (2018)

Article Multidisciplinary Sciences

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Ricard Garcia-Carbonell et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2018)

Article Multidisciplinary Sciences

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Stephanie A. Conos et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2017)

Article Biochemistry & Molecular Biology

Pathogen-induced ubiquitin-editing enzyme A20 bifunctionally shuts off NF-κB and caspase-8-dependent apoptotic cell death

Michelle C. C. Lim et al.

CELL DEATH AND DIFFERENTIATION (2017)

Review Biochemistry & Molecular Biology

The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways

Philip Cohen et al.

CELL DEATH AND DIFFERENTIATION (2017)

Article Multidisciplinary Sciences

Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Ingrid E. Wertz et al.

NATURE (2015)

Review Biochemistry & Molecular Biology

Mechanisms and Functions of Inflammasomes

Mohamed Lamkanfi et al.

Article Multidisciplinary Sciences

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

Lieselotte Vande Walle et al.

NATURE (2014)

Review Medicine, General & Internal

Necroptosis

Andreas Linkermann et al.

NEW ENGLAND JOURNAL OF MEDICINE (2014)

Article Immunology

A20-mediated negative regulation of canonical NF-κB signaling pathway

Rajeshree Pujari et al.

IMMUNOLOGIC RESEARCH (2013)

Review Biochemistry & Molecular Biology

The Ubiquitin Code

David Komander et al.

ANNUAL REVIEW OF BIOCHEMISTRY, VOL 81 (2012)

Review Immunology

Regulation of NF-κB signaling by the A20 deubiquitinase

Noula Shembade et al.

CELLULAR & MOLECULAR IMMUNOLOGY (2012)

Review Immunology

It takes two to tango: IκBs, the multifunctional partners of NF-κB

Michael Hinz et al.

IMMUNOLOGICAL REVIEWS (2012)

Review Immunology

Regulation of NF-κB by deubiquitinases

Edward W. Harhaj et al.

IMMUNOLOGICAL REVIEWS (2012)

Article Multidisciplinary Sciences

RIP3 mediates the embryonic lethality of caspase-8-deficient mice

William J. Kaiser et al.

NATURE (2011)

Article Multidisciplinary Sciences

Functional complementation between FADD and RIP1 in embryos and lymphocytes

Haibing Zhang et al.

NATURE (2011)

Editorial Material Cell Biology

A20 inhibition of NFκB and inflammation Targeting E2:E3 ubiquitin enzyme complexes

Noula Shembade et al.

CELL CYCLE (2010)

Article Multidisciplinary Sciences

Inhibition of NF-κB Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

Noula Shembade et al.

SCIENCE (2010)

Article Biochemistry & Molecular Biology

TRAF6 and A20 Regulate Lysine 63-Linked Ubiquitination of Beclin-1 to Control TLR4-Induced Autophagy

Chong-Shan Shi et al.

SCIENCE SIGNALING (2010)

Review Biochemistry & Molecular Biology

The emerging complexity of protein ubiquitination

David Komander

BIOCHEMICAL SOCIETY TRANSACTIONS (2009)

Review Immunology

Death receptor signal transducers: nodes of coordination in immune signaling networks

Nicholas S. Wilson et al.

NATURE IMMUNOLOGY (2009)

Review Cell Biology

Apoptosis: controlled demolition at the cellular level

Rebecca C. Taylor et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2008)

Article Biochemistry & Molecular Biology

IκB kinase β phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-κB pathway

Jessica E. Hutti et al.

MOLECULAR AND CELLULAR BIOLOGY (2007)