scholarly journals The FBXL family of F-box proteins: variations on a theme

Open Biology ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 200319
Author(s):  
Bethany Mason ◽  
Heike Laman
Keyword(s):  
Protein Binding ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Leucine Rich Repeat ◽  
Structural Domains ◽  
Binding Domains ◽  
Ubiquitin Proteasome ◽  
Similarities And Differences ◽  
Variations On A Theme ◽  
Lrr Protein

The ubiquitin–proteasome system (UPS) is responsible for the rapid targeting of proteins for degradation at 26S proteasomes and requires the orchestrated action of E1, E2 and E3 enzymes in a well-defined cascade. F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases that determine which proteins are ubiquitinated. To date, around 70 FBPs have been identified in humans and can be subdivided into distinct families, based on the protein-recruiting domains they possess. The FBXL subfamily is defined by the presence of multiple leucine-rich repeat (LRR) protein-binding domains. But how the 22 FBPs of the FBXL family achieve their individual specificities, despite having highly similar structural domains to recruit their substrates, is not clear. Here, we review and explore the FBXL family members in detail highlighting their structural and functional similarities and differences and how they engage their substrates through their LRRs to adopt unique interactomes.

scholarly journals Proteasome-associated ubiquitin ligase relays target plant hormone-specific transcriptional activators

2021 ◽  
Author(s):  
Zhishuo Wang ◽  
Beatriz Orosa-Puente ◽  
Mika Nomoto ◽  
Heather Grey ◽  
Thomas Potuschak ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Stress Responses ◽  
Plant Hormone ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Transcriptional Activators ◽  
Sequential Action ◽  
Ubiquitin Proteasome ◽  
Universal Mechanism ◽  
Target Plant

The ubiquitin-proteasome system is vital to hormone-mediated developmental and stress responses in plants. Ubiquitin ligases target hormone-specific transcriptional activators (TAs) for degradation, but how TAs are processed by proteasomes remains unknown. We report that in Arabidopsis the salicylic acid- and ethylene-responsive TAs, NPR1 and EIN3, are relayed from pathway-specific ubiquitin ligases to proteasome-associated HECT-type UPL3/4 ligases. Activity and stability of NPR1 was regulated by sequential action of three ubiquitin ligases, including UPL3/4, while proteasome processing of EIN3 required physical handover between ethylene-responsive SCFEBF2 and UPL3/4 ligases. Consequently, UPL3/4 controlled extensive hormone-induced developmental and stress-responsive transcriptional programmes. Thus, our findings identify unknown ubiquitin ligase relays that terminate with proteasome-associated HECT-type ligases, which may be a universal mechanism for processive degradation of proteasome-targeted TAs and other substrates.

scholarly journals Orthopoxviruses Require a Functional Ubiquitin-Proteasome System for Productive Replication

2008 ◽  
Vol 83 (5) ◽  
pp. 2099-2108 ◽  
Author(s):  
Alastair Teale ◽  
Stephanie Campbell ◽  
Nick Van Buuren ◽  
Wendy C. Magee ◽  
Kelly Watmough ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Viral Replication ◽  
Proteasome Inhibitors ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Early Gene ◽  
Late Gene Expression ◽  
Early Protein ◽  
Ubiquitin Proteasome

ABSTRACT Cellular homeostasis depends on an intricate balance of protein expression and degradation. The ubiquitin-proteasome pathway plays a crucial role in specifically targeting proteins tagged with ubiquitin for destruction. This degradation can be effectively blocked by both chemically synthesized and natural proteasome inhibitors. Poxviruses encode a number of proteins that exploit the ubiquitin-proteasome system, including virally encoded ubiquitin molecules and ubiquitin ligases, as well as BTB/kelch proteins and F-box proteins, which interact with cellular ubiquitin ligases. Here we show that poxvirus infection was dramatically affected by a range of proteasome inhibitors, including MG132, MG115, lactacystin, and bortezomib (Velcade). Confocal microscopy demonstrated that infected cells treated with MG132 or bortezomib lacked viral replication factories within the cytoplasm. This was accompanied by the absence of late gene expression and DNA replication; however, early gene expression occurred unabated. Proteasomal inhibition with MG132 or bortezomib also had dramatic effects on viral titers, severely blocking viral replication and propagation. The effects of MG132 on poxvirus infection were reversible upon washout, resulting in the production of late genes and viral replication factories. Significantly, the addition of an ubiquitin-activating enzyme (E1) inhibitor had a similar affect on late and early protein expression. Together, our data suggests that a functional ubiquitin-proteasome system is required during poxvirus infection.

scholarly journals Quantitative regulation of histone variant H2A.Z during cell cycle by ubiquitin proteasome system and SUMO-targeted ubiquitin ligases

2017 ◽  
Vol 81 (8) ◽  
pp. 1557-1560
Author(s):  
Daisuke Takahashi ◽  
Yuki Orihara ◽  
Saho Kitagawa ◽  
Masayuki Kusakabe ◽  
Takahiro Shintani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Histone Variant ◽  
Ubiquitin Proteasome

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 Role for the Ubiquitin-Proteasome System in the Vacuolar Degradation of Ste6p, the a-Factor Transporter in Saccharomyces cerevisiae

1998 ◽  
Vol 18 (2) ◽  
pp. 779-789 ◽  
Author(s):  
Diego Loayza ◽  
Susan Michaelis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Membrane Protein ◽  
Intracellular Trafficking ◽  
Ubiquitin Proteasome System ◽  
Atp Binding ◽  
Dependent Manner ◽  
Binding Domains ◽  
Ubiquitin Proteasome ◽  
Metabolic Degradation ◽  
Polytopic Membrane Protein

ABSTRACT Ste6p, the a-factor transporter in Saccharomyces cerevisiae, is a multispanning membrane protein with 12 transmembrane spans and two cytosolic ATP binding domains. Ste6p belongs to the ATP binding cassette (ABC) superfamily and provides an excellent model for examining the intracellular trafficking of a complex polytopic membrane protein in yeast. Previous studies have shown that Ste6p undergoes constitutive endocytosis from the plasma membrane, followed by delivery to the vacuole, where it is degraded in a Pep4p-dependent manner, even though only a small portion of Ste6p is exposed to the vacuolar lumen where the Pep4p-dependent proteases reside. Ste6p is known to be ubiquitinated, a modification that may facilitate its endocytosis. In the present study, we further investigated the intracellular trafficking of Ste6p, focusing on the role of the ubiquitin-proteasome machinery in the metabolic degradation of Ste6p. We demonstrate by pulse-chase analysis that the degradation of Ste6p is impaired in mutants that exhibit defects in the activity of the proteasome (doa4 andpre1,2). Likewise, by immunofluorescence, we observe that Ste6p accumulates in the vacuole in thedoa4 mutant, as it does in the vacuolar protease-deficient pep4 mutant. One model consistent with our results is that the degradation of Ste6p, the bulk of which is exposed to the cytosol, requires the activity of both the cytosolic proteasomal degradative machinery and the vacuolar lumenal proteases, acting in a synergistic fashion. Alternatively, we discuss a second model whereby the ubiquitin-proteasome system may indirectly influence the Pep4p-dependent vacuolar degradation of Ste6p. This study establishes that Ste6p is distinctive in that two independent degradative systems (the vacuolar Pep4p-dependent proteases and the cytosolic proteasome) are both involved, either directly or indirectly, in the metabolic degradation of a single substrate.

scholarly journals New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases

2014 ◽  
Vol 42 (1) ◽  
pp. 103-107 ◽  
Author(s):  
Peter Canning ◽  
Alex N. Bullock
Keyword(s):  
Drug Targets ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
E3 Ligases ◽  
Btb Domain ◽  
C Terminus ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
And Function

E3 ubiquitin ligases that direct substrate proteins to the ubiquitin–proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin–RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-à-brac) proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB–BACK (BTB and C-terminal Kelch)–Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer's disease and Parkinson's disease. Structural characterization of BTB–Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical ‘3-box’ at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways.

scholarly journals Targeting Cullin–RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

2015 ◽  
Vol 467 (3) ◽  
pp. 365-386 ◽  
Author(s):  
Emil Bulatov ◽  
Alessio Ciulli
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
Structure Assembly

In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

scholarly journals The Roles of the Ubiquitin–Proteasome System in the Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1526
Author(s):  
Junyan Qu ◽  
Tingting Zou ◽  
Zhenghong Lin
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Defense Mechanism ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Endoplasmic Reticulum Stress Pathway

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress.

Sign in / Sign up

Export Citation Format

Share Document