Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel–Lindau protein

2003 ◽  
Vol 35 (3) ◽  
pp. 229-237 ◽  
Author(s):  
Paul G Corn ◽  
E Robert McDonald ◽  
James G Herman ◽  
Wafik S El-Deiry
Keyword(s):  
Ubiquitin Ligase ◽  
Binding Protein ◽  
E3 Ubiquitin Ligase ◽  
26S Proteasome ◽  
Von Hippel Lindau ◽  
Ligase Function

scholarly journals Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pratim Chowdhury ◽  
Dimuthu Perera ◽  
Reid T. Powell ◽  
Tia Talley ◽  
Durga Nand Tripathi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Primary Cilia ◽  
Mtor Inhibitor ◽  
E3 Ubiquitin Ligase ◽  
Xenograft Model ◽  
Aurora Kinase ◽  
Tumor Burden ◽  
Aurora Kinase A ◽  
Von Hippel Lindau ◽  
In Cells

AbstractLoss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.

scholarly journals The von Hippel–Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases

2021 ◽  
Author(s):  
Gaël K. Scholtès ◽  
Aubrey M. Sawyer ◽  
Cristina C. Vaca ◽  
Isabelle Clerc ◽  
Meejeon Roh ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cytidine Deaminases ◽  
Von Hippel Lindau ◽  
Ring E3

scholarly journals E3 Ubiquitin Ligase Von Hippel–Lindau Protein Promotes Th17 Differentiation

2020 ◽  
Vol 205 (4) ◽  
pp. 1009-1023
Author(s):  
Alisha Chitrakar ◽  
Scott A. Budda ◽  
Jacob G. Henderson ◽  
Robert C. Axtell ◽  
Lauren A. Zenewicz
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Von Hippel Lindau ◽  
Th17 Differentiation

scholarly journals Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase

2020 ◽  
Vol 11 (4) ◽  
pp. 575-581 ◽  
Author(s):  
Ka Yang ◽  
Hao Wu ◽  
Zhongrui Zhang ◽  
Eric D. Leisten ◽  
Xueqing Nie ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Histone Deacetylase 6 ◽  
Von Hippel Lindau

scholarly journals A Nucleus-based Quality Control Mechanism for Cytosolic Proteins

2010 ◽  
Vol 21 (13) ◽  
pp. 2117-2127 ◽  
Author(s):  
Rupali Prasad ◽  
Shinichi Kawaguchi ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Control Systems ◽  
Ubiquitin Ligase ◽  
Nuclear Import ◽  
Control Mechanism ◽  
E3 Ubiquitin Ligase ◽  
26S Proteasome ◽  
Cytosolic Proteins ◽  
Hsp70 Chaperone ◽  
Quality Control Mechanism

Intracellular quality control systems monitor protein conformational states. Irreversibly misfolded proteins are cleared through specialized degradation pathways. Their importance is underscored by numerous pathologies caused by aberrant proteins. In the cytosol, where most proteins are synthesized, quality control remains poorly understood. Stress-inducible chaperones and the 26S proteasome are known mediators but how their activities are linked is unclear. To better understand these mechanisms, a panel of model misfolded substrates was analyzed in detail. Surprisingly, their degradation occurs not in the cytosol but in the nucleus. Degradation is dependent on the E3 ubiquitin ligase San1p, known previously to direct the turnover of damaged nuclear proteins. A second E3 enzyme, Ubr1p, augments this activity but is insufficient by itself. San1p and Ubr1p are not required for nuclear import of substrates. Instead, the Hsp70 chaperone system is needed for efficient import and degradation. These data reveal a new function of the nucleus as a compartment central to the quality control of cytosolic proteins.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, we identified and characterized wheat (Triticum aestivum) ClpS1 (TaClpS1). TaClpS1 encoded 161 amino acids, contained a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knock-down of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the growth of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

scholarly journals The ARRE RING-Type E3 Ubiquitin Ligase Negatively Regulates Cuticular Wax Biosynthesis in Arabidopsis thaliana by Controlling ECERIFERUM1 and ECERIFERUM3 Protein Levels

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuang Liu ◽  
Meixuezi Tong ◽  
Lifang Zhao ◽  
Xin Li ◽  
Ljerka Kunst
Keyword(s):  
Ubiquitin Ligase ◽  
Uv Light ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Cuticular Wax ◽  
26S Proteasome ◽  
Covalent Attachment ◽  
Wax Deposition ◽  
E3 Ligases ◽  
Ring Type

The outer epidermal cell walls of plant shoots are covered with a cuticle, a continuous lipid structure that provides protection from desiccation, UV light, pathogens, and insects. The cuticle is mostly composed of cutin and cuticular wax. Cuticular wax synthesis is synchronized with surface area expansion during plant development and is associated with plant responses to biotic and abiotic stresses. Cuticular wax deposition is tightly regulated by well-established transcriptional and post-transcriptional regulatory mechanisms, as well as post-translationally via the ubiquitin-26S proteasome system (UPS). The UPS is highly conserved in eukaryotes and involves the covalent attachment of polyubiquitin chains to the target protein by an E3 ligase, followed by the degradation of the modified protein by the 26S proteasome. A large number of E3 ligases are encoded in the Arabidopsis genome, but only a few have been implicated in the regulation of cuticular wax deposition. In this study, we have conducted an E3 ligase reverse genetic screen and identified a novel RING-type E3 ubiquitin ligase, AtARRE, which negatively regulates wax biosynthesis in Arabidopsis. Arabidopsis plants overexpressing AtARRE exhibit glossy stems and siliques, reduced fertility and fusion between aerial organs. Wax load and wax compositional analyses of AtARRE overexpressors showed that the alkane-forming branch of the wax biosynthetic pathway is affected. Co-expression of AtARRE and candidate target proteins involved in alkane formation in both Nicotiana benthamiana and stable Arabidopsis transgenic lines demonstrated that AtARRE controls the levels of wax biosynthetic enzymes ECERIFERUM1 (CER1) and ECERIFERUM3 (CER3). CER1 has also been confirmed to be a ubiquitination substrate of the AtARRE E3 ligase by an in vivo ubiquitination assay using a reconstituted Escherichia coli system. The AtARRE gene is expressed throughout the plant, with the highest expression detected in fully expanded rosette leaves and oldest stem internodes. AtARRE gene expression can also be induced by exposure to pathogens. These findings reveal that wax biosynthesis in mature plant tissues and in response to pathogen infection is controlled post-translationally.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, wheat (Triticum aestivum) ClpS1 (TaClpS1) was studied and resulted to encode 161 amino acids, containing a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in wheat resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the number of haustoria, length of infection hypha and infection area of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

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