Light-dependent phosphorylation of Bardet–Biedl syndrome 5 in photoreceptor cells modulates its interaction with arrestin1

Smith, Tyler S.; Spitzbarth, Benjamin; Li, Jian; Dugger, Donald; Stern-Schneider, Gabi; Sehn, Elisabeth; Bolch, Susan; McDowell, J. Hugh; Tipton, Jeremiah D.; Wolfrum, Uwe; Smith, W. Clay

doi:10.1007/s00018-013-1403-4

Cited by 30 publications

(25 citation statements)

References 45 publications

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“…Thus, it may cooperate with Arl6, also known as BBS3, in targeting the BBSome to specific vesicles or membrane compartments. A monoclonal antibody directed against BBS5 labels predominantly the axoneme in the outer segment, with barely detectable staining in the connecting cilium and basal body by immuno-EM, and, in contrast, co-localization in the basal body, transition zone and outer segment by immunofluorescence (Smith et al, 2013). …”

Section: Structural Organization Of the Rodmentioning

confidence: 99%

Structural and molecular bases of rod photoreceptor morphogenesis and disease

Wensel

Zhang

Anastassov

et al. 2016

Progress in Retinal and Eye Research

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The rod cell has an extraordinarily specialized structure that allows it to carry out its unique function of detecting individual photons of light. Both the structural features of the rod and the metabolic processes required for highly amplified light detection seem to have rendered the rod especially sensitive to structural and metabolic defects, so that a large number of gene defects are primarily associated with rod cell death and give rise to blinding retinal dystrophies. The structures of the rod, especially those of the sensory cilium known as the outer segment, have been the subject of structural, biochemical, and genetic analysis for many years, but the molecular bases for rod morphogenesis and for cell death in rod dystrophies are still poorly understood. Recent developments in imaging technology, such as cryo-electron tomography and super-resolution fluorescence microscopy, in gene sequencing technology, and in gene editing technology are rapidly leading to new breakthroughs in our understanding of these questions. A summary is presented of our current understanding of selected aspects of these questions, highlighting areas of uncertainty and contention as well as recent discoveries that provide new insights. Examples of structural data from emerging imaging technologies are presented.

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Section: Structural Organization Of the Rodmentioning

confidence: 99%

Structural and molecular bases of rod photoreceptor morphogenesis and disease

Wensel

Zhang

Anastassov

et al. 2016

Progress in Retinal and Eye Research

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“…Despite its importance to cilium biology, the precise subcellular location of the BBSome is unclear (29). We assessed subcellular localization of TbBBS-HA proteins by immunofluorescence (IF) and detected all fusion proteins near the base of the flagellum ( Fig.…”

Section: Tbbbsome Associates With Membranes and Vesicles At The Flagementioning

confidence: 99%

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

Langousis

Shimogawa

Saada

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cilia (eukaryotic flagella) are present in diverse eukaryotic lineages and have essential motility and sensory functions. The cilium’s capacity to sense and transduce extracellular signals depends on dynamic trafficking of ciliary membrane proteins. This trafficking is often mediated by the Bardet–Biedl Syndrome complex (BBSome), a protein complex for which the precise subcellular distribution and mechanisms of action are unclear. In humans, BBSome defects perturb ciliary membrane protein distribution and manifest clinically as Bardet–Biedl Syndrome. Cilia are also important in several parasites that cause tremendous human suffering worldwide, yet biology of the parasite BBSome remains largely unexplored. We examined BBSome functions in Trypanosoma brucei, a flagellated protozoan parasite that causes African sleeping sickness in humans. We report that T. brucei BBS proteins assemble into a BBSome that interacts with clathrin and is localized to membranes of the flagellar pocket and adjacent cytoplasmic vesicles. Using BBS gene knockouts and a mouse infection model, we show the T. brucei BBSome is dispensable for flagellar assembly, motility, bulk endocytosis, and cell viability but required for parasite virulence. Quantitative proteomics reveal alterations in the parasite surface proteome of BBSome mutants, suggesting that virulence defects are caused by failure to maintain fidelity of the host–parasite interface. Interestingly, among proteins altered are those with ubiquitination-dependent localization, and we find that the BBSome interacts with ubiquitin. Collectively, our data indicate that the BBSome facilitates endocytic sorting of select membrane proteins at the base of the cilium, illuminating BBSome roles at a critical host–pathogen interface and offering insights into BBSome molecular mechanisms.

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“…We then examined the localization of BBS proteins in normal and Cep290 fl/fl ;Cre + photoreceptors. While CEP290 is localized to the connecting cilium, BBS5 was previously shown to localize along the axoneme in the outer segment [67]. BBS5 was also detected within the connecting cilium at a lower intensity.…”

Section: Mislocalization Of Inner Segment Membrane Proteins In Cep290mentioning

confidence: 87%

CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

Datta

Hendrickson

Brendalen

et al. 2019

Preprint

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Mutations in CEP290 cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration in CEP290-associated ciliopathies are not sufficiently understood. Using Cep290 conditional mutant mice, in which the C-terminal myosin-tail homology domain is disrupted after the connecting cilium is assembled, we show that CEP290, more specifically the myosin-tail homology domain of CEP290, is essential for protein confinement between the inner and the outer segments.Inner segment plasma membrane proteins including STX3, SNAP25, and IMPG2 rapidly accumulate in the outer segment upon disruption of the myosin-tail homology domain. In contrast, localization of endomembrane proteins is not altered. Trafficking and confinement of most outer segment-resident proteins appear to be unaffected or only minimally affected in this mouse model. One notable exception is RHO, which exhibits severe mislocalization to inner segments from the initial stage of degeneration.Similar mislocalization phenotypes were observed in rd16 mice. These results suggest that failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment combined with insufficient RHO delivery is part of the disease mechanisms that cause retinal degeneration in CEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.the absence of CEP290 in these organisms, ciliary protein compositions are altered [4,6]. In mammalian primary cilia, CEP290 is localized to the transition zone [7][8][9], and loss of CEP290 reduces ARL13B and ADCY3 levels within cilia while increasing the rate of ciliary entry of SMO in fibroblasts [10]. These studies establish the current model for CEP290 function: a ciliary gatekeeper that regulates protein trafficking in and out of the ciliary compartment at the transition zone [4][5][6][7][10][11][12][13]. In photoreceptors, CEP290 is localized to the connecting cilium [14,15] and expected to control protein movement between the inner and the outer segments.Mutations in human CEP290 cause various ciliopathies ranging from isolated retinal dystrophy (e.g.Leber congenital amaurosis (LCA)) to syndromic diseases such as neonatal lethal Meckel-Gruber Syndrome (MKS) with multi-organ malformations [16][17][18][19][20][21][22]. Despite considerable variations in phenotypic severity, retinopathy is present in almost all cases regardless of the involvement of other organs. This suggests that photoreceptors are particularly susceptible to deficiencies in CEP290 function. Based on the ciliary gatekeeper model, anticipated functions of CEP290 in photoreceptors include i) permitting or facilitating entry of outer segment-bound proteins into the outer segment, ii) blocking unauthoriz...

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Light-dependent phosphorylation of Bardet–Biedl syndrome 5 in photoreceptor cells modulates its interaction with arrestin1

Cited by 30 publications

References 45 publications

Structural and molecular bases of rod photoreceptor morphogenesis and disease

Structural and molecular bases of rod photoreceptor morphogenesis and disease

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

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