scholarly journals The E3 Ubiquitin Ligase Atrophin Interacting Protein 4 Binds Directly To The Chemokine Receptor CXCR4 Via a Novel WW Domain-mediated Interaction

2009 ◽  
Vol 20 (5) ◽  
pp. 1324-1339 ◽  
Author(s):  
Deepali Bhandari ◽  
Seth L. Robia ◽  
Adriano Marchese
Keyword(s):  
Ubiquitin Ligase ◽  
Chemokine Receptor ◽  
E3 Ubiquitin Ligase ◽  
Adaptor Protein ◽  
Interacting Protein ◽  
Binding Motifs ◽  
Ww Domain ◽  
Ww Domains ◽  
Chemokine Receptor Cxcr4 ◽  
Carboxy Terminal

The E3 ubiquitin ligase atrophin interacting protein 4 (AIP4) mediates ubiquitination and down-regulation of the chemokine receptor CXCR4. AIP4 belongs to the Nedd4-like homologous to E6-AP carboxy terminus domain family of E3 ubiquitin ligases, which typically bind proline-rich motifs within target proteins via the WW domains. The intracellular domains of CXCR4 lack canonical WW domain binding motifs; thus, whether AIP4 is targeted to CXCR4 directly or indirectly via an adaptor protein remains unknown. Here, we show that AIP4 can interact directly with CXCR4 via a novel noncanonical WW domain-mediated interaction involving serine residues 324 and 325 within the carboxy-terminal tail of CXCR4. These serine residues are critical for mediating agonist-promoted binding of AIP4 and subsequent ubiquitination and degradation of CXCR4. These residues are phosphorylated upon agonist activation and phosphomimetic mutants show enhanced binding to AIP4, suggesting a mechanism whereby phosphorylation mediates the interaction between CXCR4 and AIP4. Our data reveal a novel noncanonical WW domain-mediated interaction involving phosphorylated serine residues in the absence of any proline residues and suggest a novel mechanism whereby an E3 ubiquitin ligase is targeted directly to an activated G protein-coupled receptor.

scholarly journals Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Ziying Han ◽  
Cari A. Sagum ◽  
Fumio Takizawa ◽  
Gordon Ruthel ◽  
Corbett T. Berry ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mammalian Cells ◽  
Matrix Protein ◽  
Ebola Virus ◽  
E3 Ubiquitin Ligase ◽  
Hemorrhagic Fever ◽  
Efficient Production ◽  
Ww Domain ◽  
Ww Domains ◽  
E3 Ligases

ABSTRACT Ebola virus (EBOV) is a member of the Filoviridae family and the cause of hemorrhagic fever outbreaks. The EBOV VP40 (eVP40) matrix protein is the main driving force for virion assembly and budding. Indeed, expression of eVP40 alone in mammalian cells results in the formation and budding of virus-like particles (VLPs) which mimic the budding process and morphology of authentic, infectious EBOV. To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs. In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40. We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40. Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since (i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress, (ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress, and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress. Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40. In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress. IMPORTANCE Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted. Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress.

Abstract 62: Functional analysis of endometrial cancer mutants of the E3 ubiquitin ligase adaptor protein, SPOP

2016 ◽  
Author(s):  
Fred Lozy ◽  
Mary Ellen Urick ◽  
Meghan Rudd ◽  
Deena Maurer ◽  
Daphne W. Bell
Keyword(s):  
Functional Analysis ◽  
Endometrial Cancer ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Adaptor Protein

Phosphorylation of either Ser16 or Thr30 does not disrupt the structure of the Itch E3 ubiquitin ligase third WW domain

2005 ◽  
Vol 60 (3) ◽  
pp. 558-560 ◽  
Author(s):  
Alison Z. Shaw ◽  
Pau Martin-Malpartida ◽  
Begoña Morales ◽  
Francesc Yraola ◽  
Miriam Royo ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ww Domain

scholarly journals Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets

BMC Biology ◽  
2010 ◽  
Vol 8 (1) ◽  
pp. 72 ◽  
Author(s):  
Christopher Hooper ◽  
Swamy S Puttamadappa ◽  
Zak Loring ◽  
Alexander Shekhtman ◽  
Joanna C Bakowska
Keyword(s):  
Ubiquitin Ligase ◽  
Lipid Droplets ◽  
E3 Ubiquitin Ligase ◽  
Interacting Protein

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 WW Domains from WWP2 E3 Ubiquitin Ligase Recognise Oct4 and Smad7 Peptides

2020 ◽  
Vol 118 (3) ◽  
pp. 182a
Author(s):  
Lloyd C. Wahl ◽  
Jessica E. Watt ◽  
Danielle De Bourcier ◽  
Andrew Chantry ◽  
Tharin M.A. Blumenschein
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ww Domains

scholarly journals E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKCζ

2011 ◽  
Vol 208 (10) ◽  
pp. 2099-2112 ◽  
Author(s):  
Mingjin Yang ◽  
Chen Wang ◽  
Xuhui Zhu ◽  
Songqing Tang ◽  
Liyun Shi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Quality ◽  
E3 Ubiquitin Ligase ◽  
Resistant Mutant ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Antigen Presenting ◽  
Mutant Forms

The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)–interacting protein (CHIP, also known as Stub1) is a U box–containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4– and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C ζ (PKCζ) to the TLR complex, thereby leading to activation of IL-1 receptor–associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 and 7. CHIP acts as an E3 ligase for Src and PKCζ during TLR signaling. CHIP-mediated enhancement of TLR signaling is inhibited by IFNAR deficiency or expression of ubiquitination resistant mutant forms of Src or PKCζ. These findings suggest that CHIP facilitates the formation of a TLR signaling complex by recruiting, ubiquitinating, and activating Src and PKCζ.

scholarly journals WW domain–mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex

2018 ◽  
Vol 293 (43) ◽  
pp. 16697-16708 ◽  
Author(s):  
Weiyi Yao ◽  
Zelin Shan ◽  
Aihong Gu ◽  
Minjie Fu ◽  
Zhifeng Shi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Cell Cycle Progression ◽  
Regulatory Mechanism ◽  
Cycle Progression ◽  
Hect Domain ◽  
Ww Domain ◽  
Ww Domains ◽  
E3 Ligases ◽  
Regulation Of Cell Cycle ◽  
Py Motif

The Nedd4 family E3 ligases Itch and WWP1/2 play crucial roles in the regulation of cell cycle progression and apoptosis and are closely correlated with cancer development and metastasis. It has been recently shown that the ligase activities of Itch and WWP1/2 are tightly regulated, with the HECT domain sequestered intramolecularly by a linker region connecting WW2 and WW3. Here, we show that a similar autoinhibitory mechanism is utilized by the Drosophila ortholog of Itch and WWP1/2, Suppressor of Deltex (Su(dx)). We show that Su(dx) adopts an inactive steady state with the WW domain region interacting with the HECT domain. We demonstrate that both the linker and preceding WW2 are required for the efficient binding and regulation of Su(dx) HECT. Recruiting the multiple-PY motif–containing adaptor dNdfip via WW domains relieves the inhibitory state of Su(dx) and leads to substrate (e.g. Notch) ubiquitination. Our study demonstrates an evolutionarily conservative mechanism governing the regulation and activation of some Nedd4 family E3 ligases. Our results also suggest a dual regulatory mechanism for specific Notch down-regulation via dNdfip–Su(dx)–mediated Notch ubiquitination.

scholarly journals Fat-regulated adaptor protein Dlish binds the growth suppressor Expanded and controls its stability and ubiquitination

2019 ◽  
Vol 116 (4) ◽  
pp. 1319-1324 ◽  
Author(s):  
Xing Wang ◽  
Yifei Zhang ◽  
Seth S. Blair
Keyword(s):  
Ubiquitin Ligase ◽  
Hippo Pathway ◽  
E3 Ubiquitin Ligase ◽  
Growth Control ◽  
Adaptor Protein ◽  
Domain Growth ◽  
C Terminus ◽  
The Hippo Pathway

The Drosophila protocadherin Fat controls organ size through the Hippo pathway, but the biochemical links to the Hippo pathway components are still poorly defined. We previously identified Dlish, an SH3 domain protein that physically interacts with Fat and the type XX myosin Dachs, and showed that Fat’s regulation of Dlish levels and activity helps limit Dachs-mediated inhibition of Hippo pathway activity. We here characterize a parallel growth control pathway downstream of Fat and Dlish. Using immunoprecipitation and mass spectrometry to search for Dlish partners, we find that Dlish binds the FERM domain growth repressor Expanded (Ex); Dlish SH3 domains directly bind sites in the Ex C terminus. We further show that, in vivo, Dlish reduces the subapical accumulation of Ex, and that loss of Dlish blocks the destabilization of Ex caused by loss of Fat. Moreover, Dlish can bind the F-box E3 ubiquitin ligase Slimb and promote Slimb-mediated ubiquitination of Expanded in vitro. Both the in vitro and in vivo effects of Dlish on Ex require Slimb, strongly suggesting that Dlish destabilizes Ex by helping recruit Slimb-containing E3 ubiquitin ligase complexes to Ex.

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