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Maxence V Nachury - One of the best experts on this subject based on the ideXlab platform.
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Ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia.
The Journal of cell biology, 2020Co-Authors: Swapnil Rohidas Shinde, Andrew R Nager, Maxence V NachuryAbstract:Regulated trafficking of G protein-coupled receptors (GPCRs) controls cilium-based signaling pathways. β-Arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs, but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with ubiquitin chains comprising K63 linkages (UbK63) in a β-arrestin-dependent manner before BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a UbK63-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3, and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.
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Lysine63-linked ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia
2020Co-Authors: Swapnil Rohidas Shinde, Andrew R Nager, Maxence V NachuryAbstract:Author(s): Shinde, Swapnil Rohidas; Nager, Andrew; Nachury, Maxence | Abstract: ABSTRACT Regulated trafficking of G-protein coupled receptors (GPCRs) controls cilium-based signaling pathways. β-arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl Syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with K63-linked ubiquitin (K63Ub) chains in a β-arrestin-dependent manner prior to BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a K63Ub-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3 and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that K63Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.
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Near-atomic structures of the BBSome reveal a novel mechanism for transition zone crossing
2020Co-Authors: Kriti Bahl, Shuang Yang, Hui-ting Chou, Jonathan Woodsmith, Ulrich Stelzl, Thomas Walz, Maxence V NachuryAbstract:Author(s): Bahl, Kriti; Yang, Shuang; Chou, Hui-Ting; Woodsmith, Jonathan; Stelzl, Ulrich; Walz, Thomas; Nachury, Maxence | Abstract: ABSTRACT The BBSome is a complex of eight Bardet-Biedl Syndrome (BBS) proteins that removes signaling receptors from cilia. The GTPase ARL6/BBS3 recruits the BBSome to the ciliary membrane where the BBSome–ARL6 GTP complex ferries G protein-coupled receptors (GPCRs) across the transition zone, a diffusion barrier at the base of cilia. Here, we find that the BBSome undergoes a conformational change upon recruitment to membranes by ARL6 GTP . Modeling the binding of the BBSome to membranes and to the GPCR Smoothened (SMO) reveals that the amphipathic helix 8 of SMO must be released from the membrane for SMO to be recognized by the BBSome. Underscoring the functional importance of amphipathic helix extraction in TZ crossing, we find that exchanging the amphipathic helix of ARL6 for one that embeds deeper into the membrane blocks BBSome-mediated exit of GPCRs from cilia. We propose that the rigid curvature and dense lipid packing of the transition zone reject asymmetric insertions in the inner leaflet and that the BBSome licenses transition zone crossing by extracting bulky amphipathic helices from the inner leaflet.
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BBSome trains remove activated gpcrs from cilia by enabling passage through the transition zone
Journal of Cell Biology, 2018Co-Authors: Andrew R Nager, Maxence V NachuryAbstract:A diffusion barrier at the transition zone enables the compartmentalization of signaling molecules by cilia. The BBSome and the small guanosine triphosphatase Arl6, which triggers BBSome coat polymerization, are required for the exit of activated signaling receptors from cilia, but how diffusion barriers are crossed when membrane proteins exit cilia remains to be determined. In this study, we found that activation of the ciliary G protein-coupled receptors (GPCRs) Smoothened and SSTR3 drove the Arl6-dependent assembly of large, highly processive, and cargo-laden retrograde BBSome trains. Single-molecule imaging revealed that the assembly of BBSome trains enables the lateral transport of ciliary GPCRs across the transition zone. However, the removal of activated GPCRs from cilia was inefficient because a second periciliary diffusion barrier was infrequently crossed. We conclude that exit from cilia is a two-step process in which BBSome/Arl6 trains first move activated GPCRs through the transition zone before a periciliary barrier can be crossed.
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BBSome trains remove activated gpcrs from cilia by enabling passage through the transition zone
bioRxiv, 2017Co-Authors: Andrew R Nager, Maxence V NachuryAbstract:A diffusion barrier at the transition zone enables the compartmentalization of signaling molecules by cilia. The BBSome and the small GTPase Arl6, which triggers BBSome coat polymerization, are required for the exit of activated signaling receptors from cilia, but how the BBSome coat moves cargoes out of the ciliary compartment remains poorly understood. Here we found that activation of the ciliary GPCRs Smoothened and SSTR3 drove the Arl6-dependent assembly of large, highly processive and cargo-laden retrograde BBSome trains. Single-molecule imaging revealed that the assembly of BBSome trains enabled the lateral transport of ciliary GPCRs across the transition zone. Yet, the removal of activated GPCRs from cilia was inefficient because a second, periciliary diffusion barrier was infrequently crossed. We conclude that exit from cilia is a two-step process in which the BBSome/Arl6 coat first moves activated GPCRs through the transition zone before a periciliary barrier can be crossed.
Val C Sheffield - One of the best experts on this subject based on the ideXlab platform.
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Photoreceptor cilia, in contrast to primary cilia, grant entry to a partially assembled BBSome.
Human molecular genetics, 2021Co-Authors: Ying Hsu, Seongjin Seo, Val C SheffieldAbstract:The BBSome is a protein complex consisting of BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBS18 that associates with intraflagellar transport complexes and specializes in ciliary trafficking. In primary cilia, ciliary entry requires the fully assembled BBSome as well as the small GTPase, ARL6 (BBS3). Retinal photoreceptors possess specialized cilia. In light of key structural and functional differences between primary and specialized cilia, we examined the principles of BBSome recruitment to photoreceptor cilia. We performed sucrose gradient fractionation using retinal lysates of Bbs2-/-, Bbs7-/-, Bbs8-/- and Bbs3-/- mice to determine the status of BBSome assembly, then determined localization of BBSome components using immunohistochemistry. Surprisingly, we found that a subcomplex of the BBSome containing at least BBS1, BBS5, BBS8 and BBS9 is recruited to cilia in the absence of BBS2 or BBS7. In contrast, a BBSome subcomplex consisting of BBS1, BBS2, BBS5, BBS7 and BBS9 is found in Bbs8-/- retinas and is denied ciliary entry in photoreceptor cells. In addition, the BBSome remains fully assembled in Bbs3-/- retinas and can be recruited to photoreceptor cilia in the absence of BBS3. We compared phenotypic severity of their retinal degeneration phenotypes. These findings demonstrate that unlike primary cilia, photoreceptor cilia admit a partially assembled BBSome meeting specific requirements. In addition, the recruitment of the BBSome to photoreceptor cilia does not require BBS3. These findings indicate that the ciliary entry of the BBSome is subjected to cell-specific regulation, particularly in cells with highly adapted forms of cilia such as photoreceptors.
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The absence of BBSome function decreases synaptogenesis and causes ectopic synapse formation in the retina.
Scientific Reports, 2020Co-Authors: Ying Hsu, Janelle E. Garrison, Seongjin Seo, Val C SheffieldAbstract:Photoreceptors possess ribbon synapses distinct from the conventional synapses in the brain. Little is known about the function of the BBSome, a complex integral in ciliary and intracellular trafficking, in ribbon synaptic formation. We performed immunohistochemistry using retinas from Bardet-Biedl Syndrome (BBS) mouse models and found that BBS mutant animals have significantly fewer ribbon synapses in the outer plexiform layer and increased ectopic synapses in the outer nuclear layer compared to controls. Many ectopic synapses in BBS mutant retinas are associated with horizontal cell axonal processes that aberrantly intrude into the outer nuclear layer. To determine whether this horizontal cell phenotype is a consequence of retinal degeneration, we examined this phenotype in mice with photoreceptor-specific inactivation of the BBSome induced by Cre recombinase driven by the rhodopsin promoter. At three months of age, despite retinal degeneration, Bbs8floxed/floxed; Rho-Cre+ mice lack the aberrant intrusion of horizontal cell processes. At 6 months, some horizontal cell processes intrude into the outer nuclear layer in Bbs8floxed/floxed; Rho-Cre+ mice, but the phenotype does not recapitulate the phenotypic severity observed in young congenital BBS mutant mice. Therefore, the lack of BBSome function negatively impacts retinal synaptogenesis, and causes horizontal cell defects in a potentially cell-autonomous fashion.
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Absence of BBSome function leads to astrocyte reactivity in the brain
Molecular Brain, 2019Co-Authors: Minati Singh, Janelle E. Garrison, Kai Wang, Val C SheffieldAbstract:In humans, dysfunctional primary cilia result in Bardet-Biedl syndrome (BBS), which presents with clinical features including intellectual disabilities, obesity, and retinal degeneration, and, in mouse models, the added feature of hydrocephalus. We observed increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity in BBS mouse brains. Increased GFAP expression is a hallmark of astrocyte reactivity that is associated with microglia activation and neuro-inflammation. To gain a better understanding of reactive astrocytes observed in BBS mice, we used two mouse models of BBS8, a BBSome protein, to characterize the reactive astrocyte phenotype. The finding of reactive astrocytes in young BBS mouse brains led us to hypothesize that loss of BBSome function leads to reactive astrocytes prior to hydrocephalus and obesity. By using two mouse models of BBS8, a congenital BBS8 knockout with hydrocephalus, and a tamoxifen-inducible BBS8 knockout without hydrocephalus, we were able to molecularly phenotype the reactive astrocytes. Molecular phenotype of reactive astrocytes shows differential regulation of inducers of Pan, A1 neurotoxic, and A2 neuroprotective astrocytes that are significantly altered in brains of both congenital and induced knockouts of BBS8, but without microglia activation. We find evidence for neuroinflammation in the brains of congenital knockout mice, but not in induced knockout mice. Protein levels of GFAP, SERPINA3N and post-synaptic density 95 (PSD95) are significantly increased in congenital knockout mice, but remain unchanged in induced knockout mice. Thus, despite the reactive astrocyte phenotype being present in both models, the molecular signature of reactive astrocytes in BBS8 mice models are distinct. Together, these findings suggest that BBS8, and by extension the BBSome, plays a role in neuro-astrocyte functions independent of hydrocephalus, and its dysregulation is associated with astrocyte reactivity without microglia activation. (Total word count 278).
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Abstract P459: The BBSome Mediate the Sorting of the Serotonin 5-HT2C Receptor to the Plasma Membrane in POMC Neurons
Hypertension, 2017Co-Authors: Deng-fu Guo, Qihong Zhang, Charles Searby, Val C Sheffield, Darryl Y Nishimura, Kamal RahmouniAbstract:The BBSome, a multiplex of 8 Bardet-Biedl Syndrome (BBS) proteins including BBS1, has emerged as an important regulator of energy homeostasis and cardiovascular function. Disrupting the BBSome, thr...
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The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.
PLoS genetics, 2014Co-Authors: Xitiz Chamling, Charles Searby, Diane C Slusarski, Seongjin Seo, Gunhee Kim, Val C SheffieldAbstract:Bardet-Biedl syndrome (BBS) is a well-known ciliopathy with mutations reported in 18 different genes. Most of the protein products of the BBS genes localize at or near the primary cilium and the centrosome. Near the centrosome, BBS proteins interact with centriolar satellite proteins, and the BBSome (a complex of seven BBS proteins) is believed to play a role in transporting ciliary membrane proteins. However, the precise mechanism by which BBSome ciliary trafficking activity is regulated is not fully understood. Here, we show that a centriolar satellite protein, AZI1 (also known as CEP131), interacts with the BBSome and regulates BBSome ciliary trafficking activity. Furthermore, we show that AZI1 interacts with the BBSome through BBS4. AZI1 is not involved in BBSome assembly, but accumulation of the BBSome in cilia is enhanced upon AZI1 depletion. Under conditions in which the BBSome does not normally enter cilia, such as in BBS3 or BBS5 depleted cells, knock down of AZI1 with siRNA restores BBSome trafficking to cilia. Finally, we show that azi1 knockdown in zebrafish embryos results in typical BBS phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay. These findings associate AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a novel BBS candidate gene.
Andrew R Nager - One of the best experts on this subject based on the ideXlab platform.
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Ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia.
The Journal of cell biology, 2020Co-Authors: Swapnil Rohidas Shinde, Andrew R Nager, Maxence V NachuryAbstract:Regulated trafficking of G protein-coupled receptors (GPCRs) controls cilium-based signaling pathways. β-Arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs, but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with ubiquitin chains comprising K63 linkages (UbK63) in a β-arrestin-dependent manner before BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a UbK63-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3, and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.
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Lysine63-linked ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia
2020Co-Authors: Swapnil Rohidas Shinde, Andrew R Nager, Maxence V NachuryAbstract:Author(s): Shinde, Swapnil Rohidas; Nager, Andrew; Nachury, Maxence | Abstract: ABSTRACT Regulated trafficking of G-protein coupled receptors (GPCRs) controls cilium-based signaling pathways. β-arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl Syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with K63-linked ubiquitin (K63Ub) chains in a β-arrestin-dependent manner prior to BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a K63Ub-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3 and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that K63Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.
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The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.
Structure (London England : 1993), 2019Co-Authors: Hui-ting Chou, Andrew R Nager, Susan Roehl White, Jonathan Woodsmith, Luise Apelt, Daniel P. Farrell, Vladimir Svetlov, Jaclyn S. Goldstein, Jean MullerAbstract:Summary The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-A resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.
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BBSome trains remove activated gpcrs from cilia by enabling passage through the transition zone
Journal of Cell Biology, 2018Co-Authors: Andrew R Nager, Maxence V NachuryAbstract:A diffusion barrier at the transition zone enables the compartmentalization of signaling molecules by cilia. The BBSome and the small guanosine triphosphatase Arl6, which triggers BBSome coat polymerization, are required for the exit of activated signaling receptors from cilia, but how diffusion barriers are crossed when membrane proteins exit cilia remains to be determined. In this study, we found that activation of the ciliary G protein-coupled receptors (GPCRs) Smoothened and SSTR3 drove the Arl6-dependent assembly of large, highly processive, and cargo-laden retrograde BBSome trains. Single-molecule imaging revealed that the assembly of BBSome trains enables the lateral transport of ciliary GPCRs across the transition zone. However, the removal of activated GPCRs from cilia was inefficient because a second periciliary diffusion barrier was infrequently crossed. We conclude that exit from cilia is a two-step process in which BBSome/Arl6 trains first move activated GPCRs through the transition zone before a periciliary barrier can be crossed.
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BBSome trains remove activated gpcrs from cilia by enabling passage through the transition zone
bioRxiv, 2017Co-Authors: Andrew R Nager, Maxence V NachuryAbstract:A diffusion barrier at the transition zone enables the compartmentalization of signaling molecules by cilia. The BBSome and the small GTPase Arl6, which triggers BBSome coat polymerization, are required for the exit of activated signaling receptors from cilia, but how the BBSome coat moves cargoes out of the ciliary compartment remains poorly understood. Here we found that activation of the ciliary GPCRs Smoothened and SSTR3 drove the Arl6-dependent assembly of large, highly processive and cargo-laden retrograde BBSome trains. Single-molecule imaging revealed that the assembly of BBSome trains enabled the lateral transport of ciliary GPCRs across the transition zone. Yet, the removal of activated GPCRs from cilia was inefficient because a second, periciliary diffusion barrier was infrequently crossed. We conclude that exit from cilia is a two-step process in which the BBSome/Arl6 coat first moves activated GPCRs through the transition zone before a periciliary barrier can be crossed.
Qihong Zhang - One of the best experts on this subject based on the ideXlab platform.
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Abstract P459: The BBSome Mediate the Sorting of the Serotonin 5-HT2C Receptor to the Plasma Membrane in POMC Neurons
Hypertension, 2017Co-Authors: Deng-fu Guo, Qihong Zhang, Charles Searby, Val C Sheffield, Darryl Y Nishimura, Kamal RahmouniAbstract:The BBSome, a multiplex of 8 Bardet-Biedl Syndrome (BBS) proteins including BBS1, has emerged as an important regulator of energy homeostasis and cardiovascular function. Disrupting the BBSome, thr...
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BBS mutations modify phenotypic expression of CEP290-related ciliopathies
Human molecular genetics, 2013Co-Authors: Yan Zhang, Kevin Bugge, Qihong Zhang, Charles Searby, Edwin M. Stone, Seongjin Seo, Arlene V. Drack, Sajag Bhattarai, Val C SheffieldAbstract:Ciliopathies are a group of heterogeneous disorders associated with ciliary dysfunction. Diseases in this group display considerable phenotypic variation within individual syndromes and overlapping phenotypes among clinically distinct disorders. Particularly, mutations in CEP290 cause phenotypically diverse ciliopathies ranging from isolated retinal degeneration, nephronophthisis and Joubert syndrome, to the neonatal lethal Meckel–Gruber syndrome. However, the underlying mechanisms of the variable expressivity in ciliopathies are not well understood. Here, we show that components of the BBSome, a protein complex composed of seven Bardet–Biedl syndrome (BBS) proteins, physically and genetically interact with CEP290 and modulate the expression of disease phenotypes caused by CEP290 mutations. The BBSome binds to the N-terminal region of CEP290 through BBS4 and co-localizes with CEP290 to the transition zone (TZ) of primary cilia and centriolar satellites in ciliated cells, as well as to the connecting cilium in photoreceptor cells. Although CEP290 still localizes to the TZ and connecting cilium in BBSome-depleted cells, its localization to centriolar satellites is disrupted and CEP290 appears to disperse throughout the cytoplasm in BBSome-depleted cells. Genetic interactions were tested using Cep290rd16- and Bbs4-null mutant mouse lines. Additional loss of Bbs4 alleles in Cep290rd16/rd16 mice results in increased body weight and accelerated photoreceptor degeneration compared with mice without Bbs4 mutations. Furthermore, double-heterozygous mice (Cep290+/rd16;Bbs4+/−) have increased body weight compared with single-heterozygous animals. Our data indicate that genetic interactions between BBSome components and CEP290 could underlie the variable expression and overlapping phenotypes of ciliopathies caused by CEP290 mutations.
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bbs7 is required for BBSome formation and its absence in mice results in bardet biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking
Journal of Cell Science, 2013Co-Authors: Qihong Zhang, Jianqiang Shao, Calvin S Carter, Kevin Bugge, Ruth E. Swiderski, Darryl Nishimura, Charles Searby, Timothy W Vogel, Edwin M. Stone, Val C SheffieldAbstract:Bardet-Biedl Syndrome (BBS) is a pleiotropic and genetically heterozygous disorder caused independently by numerous genes (BBS1–BBS17). Seven highly conserved BBS proteins (BBS1, 2, 4, 5, 7, 8 and 9) form a complex known as the BBSome, which functions in ciliary membrane biogenesis. BBS7 is both a unique subunit of the BBSome and displays direct physical interaction with a second BBS complex, the BBS chaperonin complex. To examine the in vivo function of BBS7, we generated Bbs7 knockout mice. Bbs7−/− mice show similar phenotypes to other BBS gene mutant mice including retinal degeneration, obesity, ventriculomegaly and male infertility characterized by abnormal spermatozoa flagellar axonemes. Using tissues from Bbs7−/− mice, we show that BBS7 is required for BBSome formation, and that BBS7 and BBS2 depend on each other for protein stability. Although the BBSome serves as a coat complex for ciliary membrane proteins, BBS7 is not required for the localization of ciliary membrane proteins polycystin-1, polycystin-2, or bitter taste receptors, but absence of BBS7 leads to abnormal accumulation of the dopamine D1 receptor to the ciliary membrane, indicating that BBS7 is involved in specific membrane protein localization to cilia.
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Intrinsic Protein-Protein Interaction-mediated and Chaperonin-assisted Sequential Assembly of Stable Bardet-Biedl Syndrome Protein Complex, the BBSome
The Journal of biological chemistry, 2012Co-Authors: Qihong Zhang, Edwin M. Stone, Seongjing Seo, Val C SheffieldAbstract:The pleiotropic features of obesity, retinal degeneration, polydactyly, kidney abnormalities, cognitive impairment, hypertension, and diabetes found in Bardet-Biedl syndrome (BBS) make this disorder an important model disorder for identifying molecular mechanisms involved in common human diseases. To date, 16 BBS genes have been reported, seven of which (BBS1, 2, 4, 5, 7, 8, and 9) code for proteins that form a complex known as the BBSome. The function of the BBSome involves ciliary membrane biogenesis. Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a complex termed the BBS-chaperonin complex. This complex is required for BBSome assembly. Little is known about the process and the regulation of BBSome formation. We utilized point mutations and null alleles of BBS proteins to disrupt assembly of the BBSome leading to the accumulation of BBSome assembly intermediates. By characterizing BBSome assembly intermediates, we show that the BBS-chaperonin complex plays a role in BBS7 stability. BBS7 interacts with BBS2 and becomes part of a BBS7-BBS2-BBS9 assembly intermediate referred to as the BBSome core complex because it forms the core of the BBSome. BBS1, BBS5, BBS8, and finally BBS4 are added to the BBSome core to form the complete BBSome.
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bardet biedl syndrome 3 bbs3 knockout mouse model reveals common bbs associated phenotypes and bbs3 unique phenotypes
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Qihong Zhang, Kevin Bugge, Charles Searby, Timothy W Vogel, Edwin M. Stone, Seongjin Seo, Donald A Morgan, Darryl Y Nishimura, Kamal Rahmouni, Val C SheffieldAbstract:Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by obesity, retinopathy, polydactyly, and congenital anomalies. The incidence of hypertension and diabetes are also increased in BBS patients. Mutation of 16 genes independently causes BBS, and seven BBS proteins form the BBSome that promotes ciliary membrane elongation. BBS3 (ARL6), an ADP ribosylation factor-like small GTPase, is not part of the BBSome complex. The in vivo function of BBS3 is largely unknown. Here we developed a Bbs3 knockout model and demonstrate that Bbs3−/− mice develop BBS-associated phenotypes, including retinal degeneration, male infertility, and increased body fat. Interestingly, Bbs3−/− mice develop some unique phenotypes not seen in other BBS knockout models: no overt obesity, severe hydrocephalus, and elevated blood pressure (shared by some but not all BBS gene knockout mice). We found that endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. This finding explains the phenotypic similarity between Bbs3−/− mice and BBSome subunit knockout mice. Loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 to ciliary membranes and affects retrograde transport of Smoothened inside cilia. We also show that the endogenous BBSome and BBS3 associate with membranes and the membrane association of the BBSome and BBS3 are not interdependent. Differences between BBS mouse models suggest nonoverlapping functions to individual BBS protein.
Kamal Rahmouni - One of the best experts on this subject based on the ideXlab platform.
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BBSome ablation in sf1 neurons causes obesity without the comorbidities
Molecular metabolism, 2021Co-Authors: Mohamed Rouabhi, Donald A Morgan, Deng-fu Guo, Justin L. Grobe, Zhiyong Zhu, Miguel López, Leonid V. Zingman, Kamal RahmouniAbstract:Abstract Objectives The hypothalamic ventromedial nucleus (VMH) is known to play a major role in metabolic control, but the molecular mechanisms involved remains poorly defined. Here, we analyzed the relevance of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, in the VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes. Methods We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1Cre/Bbs1fl/fl). We analyzed the consequence on body weight, glucose homeostasis and cardiovascular autonomic function of BBSome loss in SF1 neurons. Results We show that SF1Cre/Bbs1fl/fl mice have increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. On the other hand, SF1Cre/Bbs1fl/fl mice exhibited lower energy expenditure particularly during the dark cycle. Consistent with this, SF1Cre/Bbs1fl/fl mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1Cre/Bbs1fl/fl mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue which was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1Cre/Bbs1fl/fl mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure and baroreflex sensitivity. Conclusions Our data demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system. Our findings further reveal that the SF1 neuron BBSome is required for the development of obesity-related comorbidities.
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BBSome ablation in SF1 neurons causes obesity without comorbidities.
Molecular metabolism, 2021Co-Authors: Mohamed Rouabhi, Donald A Morgan, Deng-fu Guo, Justin L. Grobe, Zhiyong Zhu, Miguel López, Leonid V. Zingman, Kamal RahmouniAbstract:Abstract Objectives The hypothalamic ventromedial nucleus (VMH) is known to play a major role in metabolic control, but the molecular mechanisms involved remains poorly defined. Here, we analyzed the relevance of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, in the VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes. Methods We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1Cre/Bbs1fl/fl). We analyzed the consequence on body weight, glucose homeostasis and cardiovascular autonomic function of BBSome loss in SF1 neurons. Results We show that SF1Cre/Bbs1fl/fl mice have increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. On the other hand, SF1Cre/Bbs1fl/fl mice exhibited lower energy expenditure particularly during the dark cycle. Consistent with this, SF1Cre/Bbs1fl/fl mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1Cre/Bbs1fl/fl mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue which was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1Cre/Bbs1fl/fl mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure and baroreflex sensitivity. Conclusions Our data demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system. Our findings further reveal that the SF1 neuron BBSome is required for the development of obesity-related comorbidities.
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Cardiovascular Regulation by the Neuronal BBSome
Hypertension (Dallas Tex. : 1979), 2020Co-Authors: Deng-fu Guo, Donald A Morgan, John J. Reho, Kamal RahmouniAbstract:The BBSome, a complex of 8 BBS (Bardet-Biedl syndrome) proteins known for its role in the control of cilia function and other cellular processes, has been implicated in blood pressure control, but ...
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abstract 136 the ventromedial hypothalamic BBSome is required for energy homeostasis and sympathetic nerve traffic control
Hypertension, 2019Co-Authors: Deng-fu Guo, Donald A Morgan, Mohamed Rouabhi, Kamal RahmouniAbstract:The BBSome, a protein complex of 8 Bardet-Biedl Syndrome (BBS) protein including BBS1, has emerged as an important regulator of metabolic and cardiovascular function. We previously demonstrated tha...
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Smooth Muscle Cell-Specific Disruption of the BBSome Causes Vascular Dysfunction.
Hypertension (Dallas Tex. : 1979), 2019Co-Authors: John J. Reho, Donald A Morgan, Deng-fu Guo, Kamal RahmouniAbstract:The BBSome-a complex consisting of 8 Bardet-Biedl syndrome proteins-is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of Bbs1 gene-a critical component of the BBSome complex-reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle Bbs1 gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced ET-1 (endothelin-1)-induced contractility of mesenteric arteries-an effect reversed by blockade of the AT1 (angiotensin type 1 receptor) with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of renin-angiotensin system signaling.