Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B

Novas, Rossina; Cárdenas-Rodríguez, Magdalena; Lepanto, Paola; Fabregat, Matías; Rodao, Magela; Fariello, María Inés; Ramos, Maurício de Carvalho; Davison, Camila; Casanova, Gabriela; Alfaya, Lucía; Lecumberry, Federico; González‐Sapienza, Gualberto; Irigoı́n, Florencia; Badano, José L.

doi:10.1038/s41598-018-21329-6

Cited by 16 publications

(15 citation statements)

References 57 publications

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“…Additionally, Hdac6 interacts with other proteins contributing to cilia resorption such as DIDO3 and cortactin furthermore strengthening our predictions (Pinho et al, 2016). Moreover tubulin acetylation is linked to efficiency of kinesin transport along microtubules, and kinesin mutations can the affect the presence or size of cilia (Reed et al, 2006;Pooranachandran and Malicki, 2016;Balabanian et al, 2017;Novas et al, 2018). Contrary to our expectations, mutants did not show any difference in length, or number of cilia in cristae.…”

Section: Discussionsupporting

confidence: 61%

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

Łysyganicz

Pooranachandran

Liu

et al. 2021

Front. Cell Dev. Biol.

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Cilia are evolutionarily highly conserved organelles with important functions in many organs. The extracellular component of the cilium protruding from the plasma membrane comprises an axoneme composed of microtubule doublets, arranged in a 9 + 0 conformation in primary cilia or 9 + 2 in motile cilia. These microtubules facilitate transport of intraflagellar cargoes along the axoneme. They also provide structural stability to the cilium, which may play an important role in sensory cilia, where signals are received from the movement of extracellular fluid. Post-translational modification of microtubules in cilia is a well-studied phenomenon, and acetylation on lysine 40 (K40) of alpha tubulin is prominent in cilia. It is believed that this modification contributes to the stabilization of cilia. Two classes of enzymes, histone acetyltransferases and histone deacetylases, mediate regulation of tubulin acetylation. Here we use a genetic approach, immunocytochemistry and behavioral tests to investigate the function of tubulin deacetylases in cilia in a zebrafish model. By mutating three histone deacetylase genes (Sirt2, Hdac6, and Hdac10), we identify an unforeseen role for Hdac6 and Sirt2 in cilia. As expected, mutation of these genes leads to increased acetylation of cytoplasmic tubulin, however, surprisingly it caused decreased tubulin acetylation in cilia in the developing eye, ear, brain and kidney. Cilia in the ear and eye showed elevated levels of mono-glycylated tubulin suggesting a compensatory mechanism. These changes did not affect the length or morphology of cilia, however, functional defects in balance was observed, suggesting that the level of tubulin acetylation may affect function of the cilium.

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Section: Discussionsupporting

confidence: 61%

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

Łysyganicz

Pooranachandran

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…CCDC28B encoded protein is Coiled-Coil Domain Containing 28B, one of Bardet–Biedl syndrome-related proteins. CCDC28B protein localizes to centrosomes and basal bodies, wherein it plays a crucial role in ciliogenesis and cilia length regulation [ 27 , 28 ] through its interaction with kinesin-1 molecular motor [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Chen

Alhassen

Monfared

et al. 2021

IJMS

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Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia’s structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.

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“…The protein encoded by the Ccdc28b gene (coiled coil domain-containing 28B) is involved in ciliogenesis and exerts a modifier effect on Bardet-Biedl syndrome [23,24]. This syndrome is an autosomal recessive disorder, and its characteristic features include obesity, cognitive impairment, tapetoretinal degeneration, mental retardation, renal disorders, and hypertension [25,26].…”

Section: Discussionmentioning

confidence: 99%

Single-Nucleotide Polymorphisms (SNPs) Both Associated with Hypertension and Contributing to Accelerated-Senescence Traits in OXYS Rats

Devyatkin

Redina

Muraleva

et al. 2020

IJMS

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Aging is a major risk factor of numerous human diseases. Adverse genetic variants may contribute to multiple manifestations of aging and increase the number of comorbid conditions. There is evidence of links between hypertension and age-related diseases, although the genetic relationships are insufficiently studied. Here, we investigated the contribution of hypertension to the development of accelerated-senescence syndrome in OXYS rats. We compared transcriptome sequences of the prefrontal cortex, hippocampus, and retina of OXYS rats with the genotypes of 45 rat strains and substrains (which include models with hypertension) to find single-nucleotide polymorphisms (SNPs) both associated with hypertension and possibly contributing to the development of age-related diseases. A total of 725 polymorphisms were common between OXYS rats and one or more hypertensive rat strains/substrains being analyzed. Multidimensional scaling detected significant similarities between OXYS and ISIAH rat genotypes and significant differences between these strains and the other hypertensive rat strains/substrains. Nonetheless, similar sets of SNPs produce a different phenotype in OXYS and ISIAH rats depending on hypertension severity. We identified 13 SNPs causing nonsynonymous amino-acid substitutions having a deleterious effect on the structure or function of the corresponding proteins and four SNPs leading to functionally significant structural rearrangements of transcripts in OXYS rats. Among them, SNPs in genes Ephx1, Pla2r1, and Ccdc28b were identified as candidates responsible for the concomitant manifestation of hypertension and signs of accelerated aging in OXYS rats.

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Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B

Cited by 16 publications

References 57 publications

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Single-Nucleotide Polymorphisms (SNPs) Both Associated with Hypertension and Contributing to Accelerated-Senescence Traits in OXYS Rats

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