scholarly journals TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88

2021 ◽  
Vol 17 (3) ◽  
pp. e1009481
Author(s):  
Jia-qi Fang ◽  
Qian Ou ◽  
Jun Pan ◽  
Jie Fang ◽  
Da-yong Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ubiquitin Ligase ◽  
Bacterial Pathogens ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Mrna Levels ◽  
Tlr Signaling ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Myeloid Differentiation Factor

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3128-3135 ◽  
Author(s):  
Jurgen A. F. Marteijn ◽  
Laurens T. van der Meer ◽  
Liesbeth van Emst ◽  
Simon van Reijmersdal ◽  
Willemijn Wissink ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Binding Domain ◽  
U937 Cells ◽  
Dna Binding Domain ◽  
Protein Levels ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

Abstract Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.

scholarly journals The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia

2018 ◽  
Vol 29 (13) ◽  
pp. 1542-1554 ◽  
Author(s):  
Robert F. Shearer ◽  
Kari-Anne Myrum Frikstad ◽  
Jessie McKenna ◽  
Rachael A. McCloy ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Developmental Disorders ◽  
Primary Cilia ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Interacting Protein ◽  
Robust Model ◽  
Cilia Formation ◽  
Cytoplasmic Organization ◽  
Ubiquitin Proteasome

Primary cilia are crucial for signal transduction in a variety of pathways, including hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The ubiquitin–proteasome system (UPS) component UBR5 was previously identified as a putative positive regulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 ubiquitin ligase that is frequently deregulated in tumors, but its biological role in cancer is largely uncharacterized, partly due to a lack of understanding of interacting proteins and pathways. We validated the effect of UBR5 depletion on primary cilia formation using a robust model of ciliogenesis, and identified CSPP1, a centrosomal and ciliary protein required for cilia formation, as a UBR5-interacting protein. We show that UBR5 ubiquitylates CSPP1, and that UBR5 is required for cytoplasmic organization of CSPP1-comprising centriolar satellites in centrosomal periphery, suggesting that UBR5-mediated ubiquitylation of CSPP1 or associated centriolar satellite constituents is one underlying requirement for cilia expression. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

scholarly journals Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP

2012 ◽  
Vol 444 (3) ◽  
pp. 581-590 ◽  
Author(s):  
Xue-Yuan Dong ◽  
Xiaoying Fu ◽  
Songqing Fan ◽  
Peng Guo ◽  
Dan Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Breast Development ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Dependent Cell ◽  
Proteasome Pathway

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen–ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen–ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin–proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen–ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.

Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 100-108 ◽  
Author(s):  
Jurgen A. F. Marteijn ◽  
Laurens T. van der Meer ◽  
Liesbeth Van Emst ◽  
Theo de Witte ◽  
Joop H. Jansen ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Myeloid Differentiation ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Monocytic Cell ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Monocytic Lineage

Abstract Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1−/− mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1−/− mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPα, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.

scholarly journals ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20

2018 ◽  
Vol 498 (1) ◽  
pp. 72-78 ◽  
Author(s):  
Benjamin A. Portney ◽  
Raju Khatri ◽  
W. Alex Meltzer ◽  
Jennifer M. Mariano ◽  
Michal Zalzman
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

SCFβ-TRCP Mediates Ubiquitination and Degradation of the Erythropoietin Receptor and Controls Cell Proliferation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 464-464
Author(s):  
Frederique Verdier ◽  
Laure Meyer ◽  
Benedicte Deau ◽  
Hana Forejtnikova ◽  
Dominique Dumenil ◽  
...  
Keyword(s):  
Binding Site ◽  
Ubiquitin Ligase ◽  
Blood Cells ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitors ◽  
Ubiquitin Proteasome ◽  
Binding Sequence ◽  
Stimulation Of

Abstract Control of intensity and duration of erythropoietin (Epo) signalling is necessary to tightly regulate red blood cells production. After Epo stimulation of erythroid cells, 2 types of signal are transduced via the Epo receptor (Epo-R): positive signals involved in survival and proliferation, and negative signals involved in signal arrest. We have recently shown that the ubiquitin/ proteasome system plays a major role in the control of Epo-R signalling duration and desensitisation processes. Indeed, after Epo stimulation the Epo-R is ubiquitinated and its intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor, together with associated Epo is internalised and degraded by the lysosomes (Walrafen et al 2005 Blood, 105, 600-608). Our aim was to identify the E3 ubiquitin ligase involved in Epo-R ubiquitination. The Epo-R contains a putative β-Trcp binding site in its intracellular domain. Interestingly, this putative binding sequence is located in a region of the Epo-R that is deleted in erythroid progenitors from patients with familial polycythemia. We show that β-Trcp is responsible for Epo-R ubiquitination upon Epo stimulation. After Epo stimulation, β-Trcp binds to the Epo-R and this binding is dependent on Jak2 activation. Mutation of the Ser 462 residue of the Epo-R, located in the consensus β-Trcp binding site abolished β-Trcp binding, Epo-R ubiquitination and EpoR cleavage by the proteasome. Activation of the mutated Epo-R is prolonged in comparaison with Epo-R WT and BaF3 cells expressing this mutated receptor unable to bind β-Trcp are hypersensitive to Epo. Whether the removal of the β-Trcp binding site contributes to the hypersensitivity to Epo in familial polycythemia is currently under study.]

scholarly journals The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5938
Author(s):  
Jeongkwan Hong ◽  
Minho Won ◽  
Hyunju Ro
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Intercellular Signaling ◽  
Cellular Functions ◽  
Ring Type ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.

scholarly journals Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

2021 ◽  
Vol 11 (12) ◽  
pp. 1309
Author(s):  
Annarita Fiorillo ◽  
Veronica Morea ◽  
Gianni Colotti ◽  
Andrea Ilari
Keyword(s):  
Small Molecules ◽  
Ubiquitin Ligase ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Aggregate Formation ◽  
Gene Encoding ◽  
Exon 1 ◽  
Ubiquitin Proteasome ◽  
Abnormal Expansion

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS), which has been shown to play a more important role than the autophagy–lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure–function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell.

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