scholarly journals Arabidopsis ROOT PHOTOTROPISM2 is a Light-Dependent Dynamic Modulator of Phototropin1

2019 ◽  
Author(s):  
Taro Kimura ◽  
Tomoko Tsuchida-Mayama ◽  
Hirotatsu Imai ◽  
Koji Okajima ◽  
Kosuke Ito ◽  
...  
Keyword(s):  
Blue Light ◽  
Dependent Manner ◽  
Light Responses ◽  
Arabidopsis Root ◽  
Activation Level ◽  
Molecular Rheostat ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Biochemical Analyses ◽  
First Time

ABSTRACTArabidopsis thaliana phototropin1 (phot1) is a blue-light photoreceptor, i.e. a blue-light-activated Ser/Thr-protein kinase that mediates various light responses including phototropism. Phot1 functions in hypocotyl phototropism dependent on the light induction of ROOT PHOTOTROPISM2 (RPT2) proteins within a broad range of blue light intensities. It is not yet known however how RPT2 contributes to the photosensory adaptation of phot1 to high intensity blue light and the second positive phototropism. We here show that RPT2 suppresses the activity of phot1. Yeast two-hybrid analysis indicated RPT2 binding to the LOV1 (light, oxygen or voltage sensing 1) domain of phot1 required for its high photosensitivity. Our biochemical analyses revealed that RPT2 inhibits the autophosphorylation of phot1, suggesting that it suppresses the photosensitivity and/or kinase activity of phot1 through the inhibition of LOV1 function. We found for the first time that RPT2 proteins are degraded via a ubiquitin-proteasome pathway when phot1 is inactive and stabilized under blue-light conditions in a phot1-dependent manner. We propose that RPT2 is a molecular rheostat that maintains a moderate activation level of phot1 under any light intensity conditions.

scholarly journals Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

2004 ◽  
Vol 199 (11) ◽  
pp. 1545-1557 ◽  
Author(s):  
Francesca Bernassola ◽  
Paolo Salomoni ◽  
Andrew Oberst ◽  
Charles J. Di Como ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Primary Cells ◽  
Tumor Suppressor P53 ◽  
Ubiquitin Proteasome Pathway ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

scholarly journals SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

2004 ◽  
Vol 24 (20) ◽  
pp. 9092-9101 ◽  
Author(s):  
Bao Q. Vuong ◽  
Teresita L. Arenzana ◽  
Brian M. Showalter ◽  
Julie Losman ◽  
X. Peter Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Sh2 Domain ◽  
Cytokine Signaling ◽  
20S Proteasome ◽  
Signaling Proteins ◽  
Dependent Manner ◽  
Data Link ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT The regulation of cytokine signaling is critical for controlling cellular proliferation and activation during an immune response. SOCS-1 is a potent inhibitor of Jak kinase activity and of signaling initiated by several cytokines. SOCS-1 protein levels are tightly regulated, and recent data suggest that SOCS-1 may regulate the protein levels of some signaling proteins by the ubiquitin proteasome pathway; however, the cellular mechanism by which SOCS-1 directs proteins for degradation is unknown. In this report, SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC. Overexpression of SOCS-1 targets Jak1 in an SH2-dependent manner to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Analysis of MTOCs fractionated from SOCS-1-deficient cells demonstrates that SOCS-1 may function redundantly to regulate the localization of Jak1 to the MTOC. Nocodazole inhibits the protein turnover of SOCS-1, demonstrating that the minus-end transport of SOCS-1 to the MTOC-associated 20S proteasome is required to regulate SOCS-1 protein levels. These data link SOCS-1 directly with the proteasome pathway and suggest another function for the SH2 domain of SOCS-1 in the regulation of Jak/STAT signaling.

scholarly journals Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner

2003 ◽  
Vol 8 (11) ◽  
pp. 889-896 ◽  
Author(s):  
Takayuki Hattori ◽  
Kyoko Kitagawa ◽  
Chiharu Uchida ◽  
Toshiaki Oda ◽  
Masatoshi Kitagawa
Keyword(s):  
Cell Cycle ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

scholarly journals The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

PLoS Biology ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. e3001281
Author(s):  
Jung Mi Park ◽  
Seung Wook Yang ◽  
Wei Zhuang ◽  
Asim K. Bera ◽  
Yan Liu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Nonreceptor Tyrosine Kinase ◽  
Akt Activation ◽  
Fk506 Binding Protein ◽  
Human Cancers ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

scholarly journals Proteasome-mediated degradation of collagen III by cortisol in amnion fibroblasts

2018 ◽  
Vol 60 (2) ◽  
pp. 45-54 ◽  
Author(s):  
Yabing Mi ◽  
Wangsheng Wang ◽  
Jiangwen Lu ◽  
Chuyue Zhang ◽  
Yawei Wang ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Fetal Membranes ◽  
Protein Abundance ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Amnion ◽  
Collagen Iii ◽  
Transcription Inhibitor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Rupture of fetal membranes (ROM) can initiate parturition at both term and preterm. Collagen III in the compact layer of the amnion contributes to the tensile strength of fetal membranes. However, the upstream signals triggering collagen III degradation remain mostly elusive. In this study, we investigated the role of cortisol regenerated by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in collagen III degradation in human amnion fibroblasts with an aim to seek novel targets for the prevention of preterm premature ROM (pPROM)-elicited preterm birth. Human amnion tissue and cultured amnion tissue explants and amnion fibroblasts were used to study the regulation of collagen III, which is composed of three identical 3α 1 chains (COL3A1), by cortisol. Cortisol decreased COL3A1 protein but not mRNA abundance in a concentration-dependent manner. Cortisone also decreased COL3A1 protein, which was blocked by 11β-HSD1 inhibition. The reduction in COL3A1 protein by cortisol was not affected by a transcription inhibitor but was further enhanced by a translation inhibitor. Autophagic pathway inhibitor chloroquine or siRNA-mediated knock-down of ATG7, an essential protein for autophagy, failed to block cortisol-induced reduction in COL3A1 protein abundance, whereas proteasome pathway inhibitors MG132 and bortezomib significantly attenuated cortisol-induced reduction in COL3A1 protein abundance. Moreover, cortisol increased COL3A1 ubiquitination and the reduction of COL3A1 protein by cortisol was blocked by PYR-41, a ubiquitin-activating enzyme inhibitor. Conclusively, cortisol regenerated in amnion fibroblasts may be associated with ROM at parturition by reducing collagen III protein abundance through a ubiquitin-proteasome pathway.

scholarly journals NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaozhen Zhang ◽  
Xing Huang ◽  
Jian Xu ◽  
Enliang Li ◽  
Mengyi Lao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Immunotherapy ◽  
Pancreatic Tumors ◽  
Binding Motif ◽  
Dependent Manner ◽  
Substantial Impact ◽  
Post Translational Modifications ◽  
Programmed Cell Death 1 ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

AbstractDespite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically “hot” pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.

scholarly journals Serum-dependent and independent regulation of PARP2

2018 ◽  
Author(s):  
Qizhi Sun ◽  
Mohamed I. Gatie ◽  
Gregory M. Kelly
Keyword(s):  
Cell Differentiation ◽  
Insoluble Fraction ◽  
Dependent Manner ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Serum Dependent ◽  
T Cell Maturation ◽  
Serum Response

AbstractPARP2 belongs to a family of proteins involved in cell differentiation, DNA damage repair, cellular energy expenditure, chromatin modeling and cell differentiation. In addition to these overlapping functions with PARP1, PARP2 participates in spermatogenesis, T-cell maturation, extraembryonic endoderm formation and adipogenesis. The function(s) of PARP2 is far from complete, and the mechanism(s) by which the gene and protein are regulated are unknown. In this study, we found that two different mechanisms are used in vitro to regulate PARP2 levels. In the presence of serum, PARP2 is degraded through the ubiquitin-proteasome pathway, however, when serum is removed, PARP2 is rapidly sequestered into an SDS- and urea-insoluble fraction. This sequestration is relieved by serum in a dose-dependent manner, and again PARP2 is detected by immunoblotting. Furthermore, and despite the presence of a putative serum response element in the PARP2 gene, transcription is not affected by serum deprivation. These observations that PARP2 is tightly regulated by distinct pathways highlights the critical roles PARP2 plays under different physiological conditions.

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

scholarly journals Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3577
Author(s):  
Maria S. Manola ◽  
Sentiljana Gumeni ◽  
Ioannis P. Trougakos
Keyword(s):  
Accelerated Aging ◽  
Model Organisms ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Age Related ◽  
Wide Range ◽  
Transgenic Lines ◽  
Ubiquitin Proteasome ◽  
Increased Sensitivity ◽  
Proteasome Pathway

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.

scholarly journals Avian Metapneumovirus Subgroup C Induces Mitochondrial Antiviral Signaling Protein Degradation through the Ubiquitin-Proteasome Pathway

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1990
Author(s):  
Lei Hou ◽  
Xiaohan Hu ◽  
Jinshuo Guo ◽  
Rong Quan ◽  
Li Wei ◽  
...  
Keyword(s):  
Interaction Mechanism ◽  
Vero Cells ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Antiviral Signaling ◽  
Avian Metapneumovirus ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Mitochondrial Antiviral Signaling

The mitochondrial antiviral signaling (MAVS) protein, a critical adapter, links the upstream recognition of viral RNA to downstream antiviral signal transduction. However, the interaction mechanism between avian metapneumovirus subgroup C (aMPV/C) infection and MAVS remains unclear. Here, we confirmed that aMPV/C infection induced a reduction in MAVS expression in Vero cells in a dose-dependent manner, and active aMPV/C replication was required for MAVS decrease. We also found that the reduction in MAVS occurred at the post-translational level rather than at the transcriptional level. Different inhibitors were used to examine the effect of proteasome or autophagy on the regulation of MAVS. Treatment with a proteasome inhibitor MG132 effectively blocked MAVS degradation. Moreover, we demonstrated that MAVS mainly underwent K48-linked ubiquitination in the presence of MG132 in aMPV/C-infected cells, with amino acids 363, 462, and 501 of MAVS being pivotal sites in the formation of polyubiquitin chains. Finally, E3 ubiquitin ligases for MAVS degradation were screened and identified and RNF5 targeting MAVS at Lysine 363 and 462 was shown to involve in MAVS degradation in aMPV/C-infected Vero cells. Overall, these results reveal the molecular mechanism underlying aMPV/C infection-induced MAVS degradation by the ubiquitin-proteasome pathway.

Sign in / Sign up

Export Citation Format

Share Document