Regulation of primary cilia formation by the ubiquitin–proteasome system

2016 ◽  
Vol 44 (5) ◽  
pp. 1265-1271 ◽  
Author(s):  
Robert F. Shearer ◽  
Darren N. Saunders
Keyword(s):  
Signal Transduction ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Signal Transduction Pathways ◽  
Vertebrate Cell ◽  
Cilia Formation ◽  
Ubiquitin Proteasome ◽  
Novel Therapeutic

Primary cilia form at the surface of most vertebrate cell types, where they are essential signalling antennae for signal transduction pathways important for development and cancer, including Hedgehog. The importance of primary cilia in development is clearly demonstrated by numerous disorders (known as ciliopathies) associated with disrupted cilia formation (ciliogenesis). Recent advances describing functional regulators of the primary cilium highlight an emerging role for the ubiquitin–proteasome system (UPS) as a key regulator of ciliogenesis. Although there are well-documented examples of E3 ubiquitin ligases and deubiquitases in the regulation of cilia proteins, many putative components remain unvalidated. This review explores current understanding of how the UPS influences primary cilia formation, and also how recent screen data have identified more putative regulators of the UPS. Emerging research has identified many promising leads in the search for regulators of this important organelle and may identify potential novel therapeutic targets for intervention in cancer and other disease contexts.

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 Exploring the Spectrum of Kidney Ciliopathies

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1099
Author(s):  
Matteo Santoni ◽  
Francesco Piva ◽  
Alessia Cimadamore ◽  
Matteo Giulietti ◽  
Nicola Battelli ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Kidney Diseases ◽  
Ubiquitin Proteasome System ◽  
Polycystic Kidney ◽  
Ubiquitin Proteasome ◽  
Autosomal Dominant Polycystic Kidney

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

scholarly journals The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia formation via ubiquitylation of CSPP-L

2016 ◽  
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

AbstractPrimary 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 modulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 Ubiquitin ligase that is frequently deregulated in tumours, but its biological role in cancer is largely uncharacterised, 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. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

scholarly journals Hedgehog signaling and the primary cilium: implications for spatial and temporal constraints on signaling

Development ◽  
2021 ◽  
Vol 148 (9) ◽  
Author(s):  
Emily K. Ho ◽  
Tim Stearns
Keyword(s):  
Signal Transduction ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Cell Types ◽  
Spatial Constraints ◽  
Vertebrate Cell ◽  
Temporal And Spatial ◽  
Hedgehog Signal Transduction ◽  
Hedgehog Signal

ABSTRACT The mechanisms of vertebrate Hedgehog signaling are linked to the biology of the primary cilium, an antenna-like organelle that projects from the surface of most vertebrate cell types. Although the advantages of restricting signal transduction to cilia are often noted, the constraints imposed are less frequently considered, and yet they are central to how Hedgehog signaling operates in developing tissues. In this Review, we synthesize current understanding of Hedgehog signal transduction, ligand secretion and transport, and cilia dynamics to explore the temporal and spatial constraints imposed by the primary cilium on Hedgehog signaling in vivo.

scholarly journals Ochratoxin A Sequentially Activates Autophagy and the Ubiquitin-Proteasome System

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 615
Author(s):  
Akpinar ◽  
Kahraman ◽  
Yaman
Keyword(s):  
Ochratoxin A ◽  
Early Time ◽  
Human Kidney ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Mouse Embryonic Fibroblast ◽  
Proteasomal Activity ◽  
Ubiquitin Proteasome ◽  
Autophagic Activity ◽  
Sustained Activation

Ochratoxin A (OTA) is a carcinogenic mycotoxin, which is produced by Aspergillus and Penicillium genera of fungi and commonly contaminates food and feed. We and others have previously shown that OTA causes sustained activation of PI3K/AKT and MAPK/ERK1-2 signaling pathways in different cell types and animal models. Given the close relationship between cellular signaling activity and protein stability, we were curious whether increased PI3K/AKT and MAPK/ERK1-2 signaling may be the result of OTA-stimulated alterations in proteolytic activity. We show that both of the major proteolytic systems, autophagy, and the ubiquitin-proteasome system (UPS), are activated upon OTA exposure in human kidney proximal tubule HK-2 and mouse embryonic fibroblast (MEF) cells. OTA stimulates transient autophagic activity at early time points of treatment but autophagic activity subsides after 6 h even in the sustained presence of OTA. Interestingly, OTA exposure also results in increased cell death in wild-type MEF cells but not in autophagy-halted Atg5-deficient cells, suggesting that autophagy exerts a pro-death effect on OTA-induced cytotoxicity. In addition, prolonged OTA exposure decreased ubiquitinated protein levels by increasing proteasomal activity. Using purified and cellular proteasomes, we observed enhanced chymotrypsin-, caspase-, and trypsin-like activities of the 26S but not the 20S proteasome in the presence of OTA. However, in the cellular context, increased proteasomal activity depended on prior induction of autophagy. Our results suggest that autophagy and subsequent UPS activation are responsible for sustained activation of PI3K/AKT and MAPK/ERK1-2 pathways through regulating the levels of critical phosphatases VHR/DUSP3, DUSP4, and PHLPP, which are known to be involved in OTA toxicity and carcinogenicity.

Use of Ubiquitin-Proteasome System Profiling for Differentiating Between Various Leukemic Processes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4712-4712
Author(s):  
Ke Zhang ◽  
Hagop M. Kantarjian ◽  
Wanlong Ma ◽  
XI Zhang ◽  
Xiuqiang Wang ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Direct Analysis ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Lymphocytic Leukemia ◽  
Ubiquitin Proteasome

Abstract Abstract 4712 The ubiquitin-proteasome system (UPS) plays a major role in cell homeostasis in normal and neoplastic states. Expression and function of the UPS system vary with the specific characteristics of individual cell types, suggesting that determination of UPS “signatures” could be useful in identifying various cell populations. Since direct analysis of cancer cells is often problematic, even in hematologic diseases, we explored the potential of using UPS signatures in plasma to differentiate between various leukemias. We first analyzed plasma UPS profiles of patients with acute myeloid leukemia (AML; n=111), acute lymphoblastic leukemia (ALL; n=29), advanced myelodysplastic syndrome (MDS; n=20), chronic lymphocytic leukemia (CLL; n=118), or chronic myeloid leukemia (CML; n=128; 46 in accelerated/blast crisis [ACC/BL], 82 in chronic phase), and 85 healthy control subjects. Plasma levels of proteasome, ubiquitin (poly-ubiquitin), and the 3 proteasome enzymatic activities (chymotrypsin-like [Ch-L], caspase-like [Cas-L], trypsin-like [Tr-L]) were measured. Specific activities were calculated by normalizing each of the 3 enzyme activities to the levels of proteasome protein in plasma (Ch-L/p, Cas-L/p, and Tr-L/p). These 8 variables were used in multivariate logistic regression models to differentiate between leukemic processes. UPS signatures provided clear differentiation between patients with a leukemic process and normal controls (AUC=0.991), using 6 different variables (Tr-L/P, Ch-L, Ch-L/p, Cas-L, Cas-L/P, ubiquitin). Distinguishing between acute (AML, ALL, MDS) and chronic (CML, CLL) processes was less efficient (AUC=0.853 using Tr-L, Tr-L/P, Cas-L/P, Ch-L/P, proteasome, Ch-L), likely due to the high proportion (36%) of CML patients in ACC/BL phase. However, UPS signatures generally yielded powerful differentiation between individual leukemias (Table). MDS was not well differentiated from AML (AUC=0.791), reflecting the significant biological overlap of these diseases. These data support the potential usefulness of the UPS profile to aid in the differential diagnosis of various leukemias. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Attila Lehotzky ◽  
Judit Oláh ◽  
János Tibor Fekete ◽  
Tibor Szénási ◽  
Edit Szabó ◽  
...  
Keyword(s):  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Alpha Synuclein ◽  
Human Cells ◽  
Proteolytic Degradation ◽  
Intrinsically Disordered ◽  
Cell Transmission ◽  
Key Factor ◽  
Ubiquitin Proteasome ◽  
Combined Strategy

The pathological association of alpha-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25) is a key factor in the etiology of synucleinopathies. In normal brains, the intrinsically disordered SYN and TPPP/p25 are not found together but exist separately in neurons and oligodendrocytes, respectively; in pathological states, however, they are found in both cell types due to their cell-to-cell transmission. The autophagy degradation of the accumulated/assembled SYN has been considered as a potential therapeutic target. We have shown that the hetero-association of SYN with TPPP/p25 after their uptake from the medium by human cells (which mimics cell-to-cell transmission) inhibits both their autophagy- and the ubiquitin-proteasome system-derived elimination. These results were obtained by ELISA, Western blot, FACS and immunofluorescence confocal microscopy using human recombinant proteins and living human cells; ANOVA statistical analysis confirmed that TPPP/p25 counteracts SYN degradation by hindering the autophagy maturation at the stage of LC3B-SQSTM1/p62-derived autophagosome formation and its fusion with lysosome. Recently, fragments of TPPP/p25 that bind to the interface between the two hallmark proteins have been shown to inhibit their pathological assembly. In this work, we show that the proteolytic degradation of SYN on its own is more effective than when it is complexed with TPPP/p25. The combined strategy of TPPP/p25 fragments and proteolysis may ensure prevention and/or elimination of pathological SYN assemblies.

scholarly journals KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Petra Pejskova ◽  
Madeline Louise Reilly ◽  
Lucia Bino ◽  
Ondrej Bernatik ◽  
Linda Dolanska ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
Aurora A ◽  
Pathway Activation ◽  
Cilia Formation ◽  
Tightly Coupled ◽  
Hh Signaling

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

scholarly journals Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 217 ◽  
Author(s):  
Milic ◽  
Tian ◽  
Bernhagen
Keyword(s):  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Cop9 Signalosome ◽  
Ring E3 Ligase ◽  
Ubiquitin Proteasome ◽  
Underlying Mechanisms ◽  
Isopeptidase Activity

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-κB signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed.

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