scholarly journals Role of Dimerization in Poly-Ubiquitin Chain Formation

2010 ◽  
Vol 98 (3) ◽  
pp. 243a
Author(s):  
Benjamin W. Cook
Keyword(s):  
Ubiquitin Chain ◽  
Chain Formation

The photoassimilation of glucose in Chlorella with reference to the role of glycollic acid

1966 ◽  
Vol 165 (1001) ◽  
pp. 473-485 ◽  
Keyword(s):  
Chlorella Pyrenoidosa ◽  
Chain Formation ◽  
Glycollic Acid ◽  
Isonicotinyl Hydrazide

The photometabolism of glucose by Chlorella pyrenoidosa was studied by following the fate of exogenously supplied glucose-1- 14 C, glucose-2- 14 C and glucose-6- 14 C. The sucrose and insoluble polyglucan formed were extracted and hydrolysed. The constituent glucose units were degraded to determine the distribution of radioactivity between the six carbon atoms of the glucose chain. Formation of glycollic acid and of glycine was stimulated by a gas stream of 100% oxygen and by adding isonicotinyl hydrazide ( INH ). Although increases of glycollic acid and glycine were observed as a result of these treatments and at the expense of both sucrose and polyglucan the distribution of 14 C between the carbon atoms of the glucose units was scarcely affected. The results are discussed with particular reference to the metabolism of glycollic acid in Chlorella .

scholarly journals Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

2020 ◽  
Vol 117 (46) ◽  
pp. 28980-28991
Author(s):  
Zhihui Song ◽  
Wei Wei ◽  
Wenming Xiao ◽  
Essel D. Al-Saleem ◽  
Reza Nejati ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Strong Support ◽  
Ubiquitin Chain ◽  
Guide Rna ◽  
Barr Virus ◽  
Protein Ubiquitination ◽  
Crispr Screen ◽  
Epstein Barr

More than 70% of Epstein–Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

scholarly journals Expanding Role of Ubiquitin in Translational Control

2020 ◽  
Vol 21 (3) ◽  
pp. 1151 ◽  
Author(s):  
Shannon E. Dougherty ◽  
Austin O. Maduka ◽  
Toshifumi Inada ◽  
Gustavo M. Silva
Keyword(s):  
Translational Control ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Protein Quality ◽  
Rna Binding Proteins ◽  
Ubiquitin Chain ◽  
Molecular Aspects ◽  
And Function

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.

scholarly journals Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria A. McGuire ◽  
Tamara Ruiz-Zorrilla Diez ◽  
Christoph H. Emmerich ◽  
Sam Strickson ◽  
Maria Stella Ritorto ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Dimethyl Fumarate ◽  
Ubiquitin Chain ◽  
Chain Formation ◽  
Inflammatory Cytokine Production

scholarly journals The Vps27/Hrs/STAM (VHS) Domain of the Signal-transducing Adaptor Molecule (STAM) Directs Associated Molecule with the SH3 Domain of STAM (AMSH) Specificity to Longer Ubiquitin Chains and Dictates the Position of Cleavage

2015 ◽  
Vol 291 (4) ◽  
pp. 2033-2042 ◽  
Author(s):  
Nardeen Baiady ◽  
Prasanth Padala ◽  
Bayan Mashahreh ◽  
Einav Cohen-Kfir ◽  
Emily A. Todd ◽  
...  
Keyword(s):  
Structural Model ◽  
Sh3 Domain ◽  
Deubiquitinating Enzyme ◽  
Cleavage Rate ◽  
Ubiquitin Chain ◽  
Interacting Protein ◽  
Chain Cleavage ◽  
Substrate Cleavage ◽  
Vhs Domain

The deubiquitinating enzyme associated molecule with the SH3 domain of STAM (AMSH) is crucial for the removal of ubiquitin molecules during receptor-mediated endocytosis and lysosomal receptor sorting. AMSH interacts with signal transducing adapter molecule (STAM) 1 or 2, which enhances the activity of AMSH through an unknown mechanism. This stimulation is dependent on the ubiquitin-interacting motif of STAM. Here we investigate the specific mechanism of AMSH stimulation by STAM proteins and the role of the STAM Vps27/Hrs/STAM domain. We show that, in the presence of STAM, the length of the ubiquitin chains affects the apparent cleavage rate. Through measurement of the chain cleavage kinetics, we found that, although the kcat of Lys63-linked ubiquitin chain cleavage was comparable for di- and tri-ubiquitin, the Km value was lower for tri-ubiquitin. This increased affinity for longer chains was dependent on the Vps27/Hrs/STAM domain of STAM and required that the substrate ubiquitin chain contain homogenous Lys63-linkages. In addition, STAM directed AMSH cleavage toward the distal isopeptide bond in tri-ubiquitin chains. Finally, we generated a structural model of AMSH-STAM to show how the complex binds Lys63-linked ubiquitin chains and cleaves at the distal end. These data show how a deubiquitinating enzyme-interacting protein dictates the efficiency and specificity of substrate cleavage.

Triad1 Regulates Myelopoiesis through Different Ubiquitin Ligase Activities.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3292-3292
Author(s):  
Bert A. van der Reijden ◽  
Laurens van der Meer ◽  
Jurgen Marteijn ◽  
Theo de Witte ◽  
Joop H. Jansen
Keyword(s):  
Ubiquitin Ligase ◽  
Coiled Coil ◽  
Ring Finger ◽  
Proteasomal Degradation ◽  
Inhibitory Effect ◽  
Ring Domain ◽  
Wild Type ◽  
Ubiquitin Chain ◽  
Clonogenic Growth

Abstract The modification of cellular proteins with poly-ubiquitin chains plays an essential role in hematopoiesis. Different types of ubiquitin chains may have opposite effects on the marked proteins. Chains linked through lysine 48 of ubiquitin are recognized by the proteasome resulting in progressive degradation of the ubiquitylated proteins. Ubiquitin chains linked through lysine 63 are not recognized by the proteasome. Instead, these chains can bind proteins that regulate signal transduction and gene transcription. Although it is known that ubiquitylation is essential for hematopoiesis and that alterations in ubiquitylation have been implicated in malignant hematopoiesis the ubiquitin ligases that catalyze protein ubiquitylation remain largely unknown. Triad1 is an ubiquitin ligase that inhibits the proliferation of myeloid progenitor cells through its ligase activity. Triad1 belongs to a unique class of ligases that harbor two RING finger protein domains. This domain specifically binds ubiquitin conjugating enzymes (Ubcs). Together with the Ubcs the ligases determine which type of ubiquitin chain is catalyzed. To understand how Triad1 regulates myelopoiesis we screened a panel of Ubcs for Triad1 interaction and found that Triad1 binds UbcH7 through its N-terminal RING domain and Ubc13 through its C-terminal RING domain. UbcH7 catalyzes the formation of ubiquitin chains linked through lysine 48 that are recognized by the proteasome. Importantly, ubiquitin chains catalyzed by Ubc13 are linked through lysine 63 and are not recognized by the proteasome. In agreement with these interactions, in vitro ubiquitylation assays using different ubiquitin mutants containing only one lysine residue showed that Triad1 can catalyze the formation of both types of ubiquitin chains. The relevance of these findings in myelopoiesis was studied by generating a panel of Triad1 deletion mutants that lack the coiled coil, DRIL or RING domains. Next, the growth inhibitory effect of these mutants was tested in clonogenic assays by retroviral transduction of U937 cells. Like in primary cells, wild type Triad1 inhibited U937 colony formation by over 60% compared to empty vector transduced cells. Three Triad1 mutants lacking the DRIL domain or either one or two of the coiled coil domains inhibited clonogenic growth at a comparable rate as wild type Triad1. In contrast, deletion of either the N- or C-terminal RING finger completely abrogated the inhibitory effect of Triad1 in clonogenic growth. Thus, loss of either the UbcH7 or Ubc13 binding domain of Triad1 affects its inhibitory function in myeloid cell proliferation. Recently, we reported that Triad1 binds the transcription factor Gfi1. Gfi1 plays an important role during many hematopoietic developmental stages and is essential for neutrophilic differentiation. Remarkably, Triad1 inhibited Gfi1 ubiquitylation and proteasomal degradation. The finding here that Triad1 can catalyze the formation of different ubiquitin chains might suggest that Triad1 may modify Gfi1 with ubiquitin in a functional way, rather than marking it for proteasomal degradation. Indeed, in vivo ubiquitylation experiments showed that Gfi1 can be modified with ubiquitin chains not linked through lysine 48. The relevance of this finding and the role of Triad1 in this process is currently studied. Together, these data indicate that the dual ubiquitin ligase activity that results in the formation of different poly-ubiquitin chains is crucial to the central role of Triad1 in myelopoiesis.

scholarly journals ­­LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation

2016 ◽  
Vol 213 (12) ◽  
pp. 2671-2689 ◽  
Author(s):  
Julia Zinngrebe ◽  
Eva Rieser ◽  
Lucia Taraborrelli ◽  
Nieves Peltzer ◽  
Torsten Hartwig ◽  
...  
Keyword(s):  
Cell Death ◽  
Influenza A ◽  
Gene Activation ◽  
Ubiquitin Chain ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Biochemical Level ◽  
Chronic Proliferative Dermatitis ◽  
Tlr3 Signaling

The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.

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