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The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA.
DDX41 is a sensor of intracellular double-stranded DNA (dsDNA) in myeloid dendritic cells (mDCs) that triggers a type I interferon response via the signaling adaptor STING. We identified the E3 ligase TRIM21 as a DDX41-interacting protein and found that knockdown of or deficiency in TRIM21 resulted in enhanced type I interferon responses to intracellular dsDNA and DNA viruses. Overexpression of TRIM21 resulted in more degradation of DDX41 and less production of interferon-β (IFN-β) in response to intracellular dsDNA. The SPRY-PRY domain of TRIM21 interacted with the DEADc domain of DDX41. Lys9 and Lys115 of DDX41 were the targets of TRIM21-mediated ubiquitination. TRIM21 is therefore an interferon-inducible E3 ligase that induces the Lys48 (K48)-linked ubiquitination and degradation of DDX41 and negatively regulates the innate immune response to intracellular dsDNA.
Document Type:

Reference

Product Catalog Number:

Multiple
Product Catalog Name:

Multiple
The ubiquitin ligase c-Cbl down-regulates FcgammaRIIa activation in human neutrophils.
Little is known about the mechanisms that arrest FcgammaRIIa signaling in human neutrophils once engaged by immune complexes or opsonized pathogens. In our previous studies, we observed a loss of immunoreactivity of Abs directed against FcgammaRIIa following its cross-linking. In this study, we report on the mechanisms involved in this event. A stimulated internalization of FcgammaRIIa leading to the down-regulation of its surface expression was observed by flow cytometry and confocal microscopy. Immunoprecipitation of the receptor showed that FcgammaRIIa is ubiquitinated after stimulation. MG132 and clasto-lactacystin beta-lactone inhibited the loss of immunoreactivity of FcgammaRIIa, suggesting that this receptor was down-regulated via the proteasomal pathway. The E3 ubiquitin ligase c-Cbl was found to translocate from the cytosol to the plasma membrane following receptor cross-linking. Furthermore, c-Cbl was recruited to the same subset of high-density, detergent-resistant membrane fractions as stimulated FcgammaRIIa itself. Silencing the expression of c-Cbl by small interfering RNA decreased FcgammaRIIa ubiquitination and prevented its degradation without affecting the internalisation process. It also prolonged the stimulation of the tyrosine phosphorylation response to the cross-linking of the receptor. We conclude that c-Cbl mediates the ubiquitination of stimulated FcgammaRIIa and thereby contributes to the termination of FcgammaRIIa signaling via its proteasomal degradation, thus leading to the down-regulation of neutrophil signalisation and function (phagocytosis) through this receptor.
Document Type:

Reference

Product Catalog Number:

Multiple
Product Catalog Name:

Multiple
The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle.
Owing to the intensive research activity on protein synthesis, little attention was paid in the 1950s and 1960s to protein degradation. However, work by my group and others between 1970 and 1990 led to the identification of the ubiquitin-dependent degradation system. We found that this system contains three types of enzymes: E1 ubiquitin--activating enzyme, E2 ubiquitin--carrier enzyme and E3 ubiquitin--protein ligase. The sequential action of these enzymes leads to conjugation of ubiquitin to proteins and then in most cases to their degradation. This review briefly tells the story of how this pathway was discovered describing the main findings that during the years allowed us to draw the complex picture we have now.
Document Type:

Reference

Product Catalog Number:

05-944
Product Catalog Name:

Anti-Ubiquitin Antibody, clone P4D1-A11
E3 ubiquitin ligase tripartite motif 38 negatively regulates TLR-mediated immune responses by proteasomal degradation of TNF receptor-associated factor 6 in macrophages.
Activation of TLR signaling in the innate immune cells is critical for the elimination of invading microorganisms. However, uncontrolled activation may lead to autoimmune and inflammatory diseases. In this article, we report the identification of tripartite motif (TRIM) 38 as a negative feedback regulator in TLR signaling by targeting TNFR-associated factor 6 (TRAF6). TRIM38 was induced by TLR stimulation in an NF-κB-dependent manner in macrophages. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of NF-κB and MAPKs, and enhanced expression of proinflammatory cytokines, whereas overexpression of TRIM38 has an opposite effect. As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. Consistently, knockdown of TRIM38 expression resulted in higher protein level of TRAF6 in primary macrophages. Our findings defined a novel function for TRIM38 to prevent excessive TLR-induced inflammatory responses through proteasomal degradation of TRAF6.
Document Type:

Reference

Product Catalog Number:

05-1307
Product Catalog Name:

Anti-Ubiquitin Antibody, Lys48-Specific, clone Apu2, rabbit monoclonal
The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination.
The ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the sirtuin family member SirT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity. In CHIP-deficient cells, SirT6 protein half-life is substantially reduced due to increased proteasome-mediated degradation, but CHIP overexpression in these cells increases SirT6 protein expression without affecting SirT6 transcription. CHIP noncanonically ubiquitinates SirT6 at K170, which stabilizes SirT6 and prevents SirT6 canonical ubiquitination by other ubiquitin ligases. In CHIP-depleted cells, SirT6 K170 mutation increases SirT6 half-life and prevents proteasome-mediated degradation. The global decrease in SirT6 expression in the absence of CHIP is associated with decreased SirT6 promoter occupancy, which increases histone acetylation and promotes downstream gene transcription in CHIP-depleted cells. Cells lacking CHIP are hypersensitive to DNA-damaging agents, but DNA repair and cell viability are rescued by enforced expression of SirT6. The discovery of this CHIP-SirT6 interaction represents a novel protein-stabilizing mechanism and defines an intersection between protein quality control and epigenetic regulation to influence pathways that regulate the biology of aging.
Document Type:

Reference

Product Catalog Number:

17-10085
Product Catalog Name:

Magna ChIP™ A/G Chromatin Immunoprecipitation Kit
E3 ubiquitin ligase synoviolin is involved in liver fibrogenesis.
Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis.The expression and localization of synoviolin in the liver were analyzed in CCl(4)-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno(+/-) mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno(+/-) mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno(-/-) mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno(-/-) MEF cells.In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno(+/-) mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno(+/-) mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno(-/-) MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.
Document Type:

Reference

Product Catalog Number:

AB765P
Product Catalog Name:

Anti-Mouse Collagen Type I Antibody
The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression.
The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.
Document Type:

Reference

Product Catalog Number:

Multiple
Product Catalog Name:

Multiple
The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.
The primary role of the innate immune response is to limit the spread of infectious pathogens, with activation of Toll-like receptor (TLR) and RIG-like receptor (RLR) pathways resulting in a pro-inflammatory response required to combat infection. Limiting the activation of these signaling pathways is likewise essential to prevent tissue injury in the host. Triad3A is an E3 ubiquitin ligase that interacts with several components of TLR signaling and modulates TLR activity. In the present study, we demonstrate that Triad3A negatively regulates the RIG-I RNA sensing pathway through Lys48-linked, ubiquitin-mediated degradation of the tumor necrosis factor receptor-associated factor 3 (TRAF3) adapter. Triad3A was induced following dsRNA exposure or virus infection and decreased TRAF3 levels in a dose-dependent manner; moreover, Triad3A expression blocked IRF-3 activation by Ser-396 phosphorylation and inhibited the expression of type 1 interferon and antiviral genes. Lys48-linked ubiquitination of TRAF3 by Triad3A increased TRAF3 turnover, whereas reduction of Triad3A expression by stable shRNA expression correlated with an increase in TRAF3 protein expression and enhancement of the antiviral response following VSV or Sendai virus infection. Triad3A and TRAF3 physically interacted together, and TRAF3 residues Y440 and Q442--previously shown to be important for association with the MAVS adapter--were also critical for Triad3A. Point mutation of the TRAF-Interacting-Motif (TIM) of Triad3A abrogated its ability to interact with TRAF3 and modulate RIG-I signaling. TRAF3 appears to undergo sequential ubiquitin "immuno-editing" following virus infection that is crucial for regulation of RIG-I-dependent signaling to the antiviral response. Thus, Triad3A represents a versatile E3 ubiquitin ligase that negatively regulates RIG-like receptor signaling by targeting TRAF3 for degradation following RNA virus infection.
Document Type:

Reference

Product Catalog Number:

MAB1501
Product Catalog Name:

Anti-Actin Antibody, clone C4
The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg
Document Type:

Reference

Product Catalog Number:

07-483
Product Catalog Name:

Anti-UBB+1 Antibody, Ubi2a
The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid.
Craniofacial anomalies (CFAs) are the most frequently occurring human congenital disease, and a major cause of infant mortality and childhood morbidity. Although CFAs seems to arise from a combination of genetic factors and environmental influences, the underlying gene defects and pathophysiological mechanisms for most CFAs are currently unknown. Here we reveal a role for the E3 ubiquitin ligase Wwp2 in regulating craniofacial patterning. Mice deficient in Wwp2 develop malformations of the craniofacial region. Wwp2 is present in cartilage where its expression is controlled by Sox9. Our studies demonstrate that Wwp2 influences craniofacial patterning through its interactions with Goosecoid (Gsc), a paired-like homeobox transcription factor that has an important role in craniofacial development. We show that Wwp2-associated Gsc is a transcriptional activator of the key cartilage regulatory protein Sox6. Wwp2 interacts with Gsc to facilitate its mono-ubiquitylation, a post-translational modification required for optimal transcriptional activation of Gsc. Our results identify for the first time a physiological pathway regulated by Wwp2 in vivo, and also a unique non-proteolytic mechanism through which Wwp2 controls craniofacial development.
Document Type:

Reference

Product Catalog Number:

AB5535
Product Catalog Name:

Anti-Sox9 Antibody