The BBSome assembly is spatially controlled by BBS1 and BBS4 in human cells

Prasai, Avishek; Černohorská, Markéta; Ruppova, Klara; Niederlová, Veronika; Andelova, Monika; Dráber, Peter; Štěpánek, Ondřej; Huranová, Martina

doi:10.1101/2020.03.20.000091

Cited by 3 publications

(4 citation statements)

References 48 publications

(78 reference statements)

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“…Interestingly, analysis of the dynamic behavior of the BBSome throughout the primary cilium demonstrated a rapid recovery (halftime of 2-6 seconds) in a photobleaching assay, indicating that the BBSome complex has a relatively fast turnover rate. 73 Said data suggest that the WT BBS1 protein is assembled de novo into the BBSome rather than replacing the mutant BBS1 protein in the pre-existing BBSome. However, further mechanistic studies are needed to better understand the dynamics of BBSome in OSNs.…”

Section: Discussionmentioning

confidence: 99%

“…Fortunately, we were able to rescue the olfactory deficits in the Bbs1 M390R/M390R mice, suggesting that proper function of the BBSome can be restored by ectopic WT Bbs1 expression. Interestingly, analysis of the dynamic behavior of the BBSome throughout the primary cilium demonstrated a rapid recovery (halftime of 2‐6 seconds) in a photobleaching assay, indicating that the BBSome complex has a relatively fast turnover rate 73 . Said data suggest that the WT BBS1 protein is assembled de novo into the BBSome rather than replacing the mutant BBS1 protein in the pre‐existing BBSome.…”

Section: Discussionmentioning

confidence: 99%

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Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet–Biedl syndrome

et al. 2021

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Bardet–Biedl syndrome (BBS) is a hereditary genetic disorder that results in numerous clinical manifestations including olfactory dysfunction. Of at least 21 BBS‐related genes that can carry multiple mutations, a pathogenic mutation, BBS1M390R, is the single most common mutation of clinically diagnosed BBS outcomes. While the deletion of BBS‐related genes in mice can cause variable penetrance in different organ systems, the impact of the Bbs1M390R mutation in the olfactory system remains unclear. Using a clinically relevant knock‐in mouse model homozygous for Bbs1M390R, we investigated the impact of the mutation on the olfactory system and tested the potential of viral‐mediated, wildtype gene replacement therapy to rescue smell loss. The cilia of olfactory sensory neurons (OSNs) in Bbs1M390R/M390R mice were significantly shorter and fewer than those of wild‐type mice. Also, both peripheral cellular odor detection and synaptic‐dependent activity in the olfactory bulb were significantly decreased in the mutant mice. Furthermore, to gain insight into the degree to which perceptual features are impaired in the mutant mice, we used whole‐body plethysmography to quantitatively measure odor‐evoked sniffing. The Bbs1M390R/M390R mice showed significantly higher odor detection thresholds (reduced odor sensitivity) compared to wild‐type mice; however, their odor discrimination acuity was still well maintained. Importantly, adenoviral expression of Bbs1 in OSNs restored cilia length and re‐established both peripheral odorant detection and odor perception. Together, our findings further expand our understanding for the development of gene therapeutic treatment for congenital ciliopathies in the olfactory system.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet–Biedl syndrome

et al. 2021

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“…Kaplan-Meier survival analysis was used to plot overall survival (OS). The hazard ratio (HR) of the 95 % confidence intervals (CI) will be computed using Cox proportional hazard regression analysis to test the relationship between BBS4 expression level and a stable protein complex, called BBSome, which is a binding protein complex composed of BBS1, 2, 4, 5, 7, 8, 9 and 18, which is structurally similar to the coat protein or adapter protein involved in vesicle transport [4][5][6] . Bardet-Biedl syndrome 4 (BBS4) is one of several proteins that cause BBSome.…”

Section: Discussionmentioning

confidence: 99%

Bardet-Biedl Syndrome 4 in Early Diagnosis and Prognosis of Breast Cancer

Zhang¹,

Suo²,

Sun³

et al. 2021

ijps

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Zhang et al.: Bardet-Biedl Syndrome 4 in Breast CancerBardet-Biedl syndrome 4 is the key protein to control cilia formation. In this study, bioinformatics method was used to screen the core genes related to the prognosis of breast cancer by analyzing the gene chip data of gene expression omnibus and the cancer genome atlas database, so as to provide a new candidate target for the treatment of breast cancer. Data were downloaded from the cancer genome atlas, gene expression omnibus to evaluate Bardet-Biedl syndrome 4 expression levels in breast cancer. Differentially expressed genes were screened by R package. Gene ontology and Kyoto encyclopedia of Genes and Genomes pathway enrichment analysis was used to explore the biological functions of differentially expressed genes. The correlation of differentially expressed genes used was, "corrplot" for visual analysis. The proteinprotein interaction relationship was constructed based on search tool for the retrieval of interacting genes/ proteins database and Cytoscape software and the key genes were obtained by module analysis with Cytoscape software molecular complex detection plugin and the prognostic value and survival of Bardet-Biedl syndrome 4 were evaluated by R package. Finally, the correlation between Bardet-Biedl syndrome 4 and clinicopathological parameters was also visualized by R package. These differentially expressed genes were mainly involved in response to peptide hormone, nuclear division, hormone secretion and transport and extracellular matrix. Genes were mainly involved in the Kyoto encyclopedia of genes and genomes pathway called Interleukin-17 signaling pathway. Bardet-Biedl syndrome 4 levels were found to be down regulated in breast cancer tissues compared with normal tissues. Survival analysis showed that low Bardet-Biedl syndrome 4 expression was associated with poor prognosis. These results were verified in clinical specimens, where in the Bardet-Biedl syndrome 4 protein levels were significantly down regulated in breast cancer tissues compared with non-breast cancer tissues. This study confirmed that Bardet-Biedl syndrome 4 can be used as an independent prognostic factor for the prognosis of breast cancer, which provides a basis for exploring a new target for the treatment of breast cancer.

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“…For this experiment, we used mechanically isolated OSs of 5 month old zygotic bbs1 -/fish and their wildtype siblings as controls (Fig. 5a), which we submitted to label-free quantitative MS-MS. BBS4 and BBS1 are thought to play a key role in the spatial regulation of the full BBSome complex assembly 51 restricting the entry of the complex into the cilium in the absence of BBS1 52 . However, a recent publication suggested that photoreceptor cilia, in contrast to primary cilia, grant entry to a partially assembled BBSome 53 .…”

Section: Accumulation Of Membrane-associated Proteins In Mutant Outer Segmentsmentioning

confidence: 99%

The Bardet-Biedl protein Bbs1 controls photoreceptor outer segment protein and lipid composition

Masek

Etard

Hofmann

et al. 2021

Preprint

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Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a new bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on isolated OSs show that Bbs1 is required for BBSome-entry into OSs and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a new role for Bbs1/BBSome in OS lipid homeostasis and suggest a new pathomechanism underlying retinal degeneration in BBS.

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The BBSome assembly is spatially controlled by BBS1 and BBS4 in human cells

Cited by 3 publications

References 48 publications

Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet–Biedl syndrome

Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet–Biedl syndrome

Bardet-Biedl Syndrome 4 in Early Diagnosis and Prognosis of Breast Cancer

The Bardet-Biedl protein Bbs1 controls photoreceptor outer segment protein and lipid composition

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