Limits...
BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors.

Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, Hu J - Sci Rep (2015)

Bottom Line: However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive.Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans.Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.

ABSTRACT
Cilia harbor sensory receptors for various signaling cascades critical for vertebrate development. However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive. Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS-4 directly interacts with BBS-5 and the interaction can be disrupted by a conserved mutation identified in human BBS4. Surprisingly, we found that BBS-4 and BBS-5 act redundantly in the BBSome to regulate the ciliary removal, rather than the ciliary entry or retrograde IFT transport, of various sensory receptors. Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS4 and BBS5 also interact directly and coordinate the ciliary removal of polycystin 2. Hence, we reveal a novel and highly conserved role for the BBSome in fine-tuning ciliary signaling by regulating the ciliary removal of sensory receptors for lysosomal degradation.

No MeSH data available.


Related in: MedlinePlus

Mislocalization and accumulation of OSM-9 and ODR-10 in bbs-4; bbs-5 and bbs-7 mutant cilia.(a) OSM-9, the TRP mechanosensory receptor channel, accumulates both inside and below OLQ cilia in bbs-4; bbs-5 and bbs-7 mutants. (b) OSM-9 accumulates inside phasmid cilia in bbs-4; bbs-5 and bbs-7 mutants. (c) Relative fluorescence intensity of OSM-9-GFP in each group shown in (b) was plotted. Yellow dashed line indicates the pixels used to measure the fluorescence intensity. (d) GPCR ODR-10 accumulates inside AWA cilia in bbs-4; bbs-5 and bbs-7 mutants. (e) Relative fluorescence intensity of ODR-10-GFP in each group shown indicated as a yellow dashed line in (d) was plotted. Arrows and arrowheads indicate the base and tip of cilia, respectively. Stars note the junction of middle and distal segment. Scale bars, 5 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493597&req=5

f2: Mislocalization and accumulation of OSM-9 and ODR-10 in bbs-4; bbs-5 and bbs-7 mutant cilia.(a) OSM-9, the TRP mechanosensory receptor channel, accumulates both inside and below OLQ cilia in bbs-4; bbs-5 and bbs-7 mutants. (b) OSM-9 accumulates inside phasmid cilia in bbs-4; bbs-5 and bbs-7 mutants. (c) Relative fluorescence intensity of OSM-9-GFP in each group shown in (b) was plotted. Yellow dashed line indicates the pixels used to measure the fluorescence intensity. (d) GPCR ODR-10 accumulates inside AWA cilia in bbs-4; bbs-5 and bbs-7 mutants. (e) Relative fluorescence intensity of ODR-10-GFP in each group shown indicated as a yellow dashed line in (d) was plotted. Arrows and arrowheads indicate the base and tip of cilia, respectively. Stars note the junction of middle and distal segment. Scale bars, 5 μm.

Mentions: To further determine whether the abnormal accumulation in bbs-4; bbs-5 cilia is a PKD-2-specific defect or a general defect for other sensory receptors, we examined two additional sensory receptors, the mechanosensory receptor TRP channel OSM-934 and the G protein-coupled receptor ODR-1035. GFP-tagged OSM-9 strongly labels the cilia of mechanosensory OLQ neurons and phasmid neurons, and GFP-tagged ODR-10 labels the fan-shaped cilia of chemosensory AWA neurons (Fig. 2). Remarkably, both OSM-9 and ODR-10 show strong accumulations, with ~6-fold increasing of protein levels in their native expressing cilia in bbs-4; bbs-5 mutants (Fig. 2). We thus concluded that BBS-4 and BBS-5 act redundantly to coordinate the proper cilia homeostasis of various sensory receptors. Moreover, the observation that comparable accumulation of PKD-2, OSM-9, and ODR-10 in bbs-7 cilia suggests the involvement of the whole BBSome in this process (Fig. 1h and 2).


BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors.

Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, Hu J - Sci Rep (2015)

Mislocalization and accumulation of OSM-9 and ODR-10 in bbs-4; bbs-5 and bbs-7 mutant cilia.(a) OSM-9, the TRP mechanosensory receptor channel, accumulates both inside and below OLQ cilia in bbs-4; bbs-5 and bbs-7 mutants. (b) OSM-9 accumulates inside phasmid cilia in bbs-4; bbs-5 and bbs-7 mutants. (c) Relative fluorescence intensity of OSM-9-GFP in each group shown in (b) was plotted. Yellow dashed line indicates the pixels used to measure the fluorescence intensity. (d) GPCR ODR-10 accumulates inside AWA cilia in bbs-4; bbs-5 and bbs-7 mutants. (e) Relative fluorescence intensity of ODR-10-GFP in each group shown indicated as a yellow dashed line in (d) was plotted. Arrows and arrowheads indicate the base and tip of cilia, respectively. Stars note the junction of middle and distal segment. Scale bars, 5 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493597&req=5

f2: Mislocalization and accumulation of OSM-9 and ODR-10 in bbs-4; bbs-5 and bbs-7 mutant cilia.(a) OSM-9, the TRP mechanosensory receptor channel, accumulates both inside and below OLQ cilia in bbs-4; bbs-5 and bbs-7 mutants. (b) OSM-9 accumulates inside phasmid cilia in bbs-4; bbs-5 and bbs-7 mutants. (c) Relative fluorescence intensity of OSM-9-GFP in each group shown in (b) was plotted. Yellow dashed line indicates the pixels used to measure the fluorescence intensity. (d) GPCR ODR-10 accumulates inside AWA cilia in bbs-4; bbs-5 and bbs-7 mutants. (e) Relative fluorescence intensity of ODR-10-GFP in each group shown indicated as a yellow dashed line in (d) was plotted. Arrows and arrowheads indicate the base and tip of cilia, respectively. Stars note the junction of middle and distal segment. Scale bars, 5 μm.
Mentions: To further determine whether the abnormal accumulation in bbs-4; bbs-5 cilia is a PKD-2-specific defect or a general defect for other sensory receptors, we examined two additional sensory receptors, the mechanosensory receptor TRP channel OSM-934 and the G protein-coupled receptor ODR-1035. GFP-tagged OSM-9 strongly labels the cilia of mechanosensory OLQ neurons and phasmid neurons, and GFP-tagged ODR-10 labels the fan-shaped cilia of chemosensory AWA neurons (Fig. 2). Remarkably, both OSM-9 and ODR-10 show strong accumulations, with ~6-fold increasing of protein levels in their native expressing cilia in bbs-4; bbs-5 mutants (Fig. 2). We thus concluded that BBS-4 and BBS-5 act redundantly to coordinate the proper cilia homeostasis of various sensory receptors. Moreover, the observation that comparable accumulation of PKD-2, OSM-9, and ODR-10 in bbs-7 cilia suggests the involvement of the whole BBSome in this process (Fig. 1h and 2).

Bottom Line: However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive.Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans.Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.

ABSTRACT
Cilia harbor sensory receptors for various signaling cascades critical for vertebrate development. However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive. Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS-4 directly interacts with BBS-5 and the interaction can be disrupted by a conserved mutation identified in human BBS4. Surprisingly, we found that BBS-4 and BBS-5 act redundantly in the BBSome to regulate the ciliary removal, rather than the ciliary entry or retrograde IFT transport, of various sensory receptors. Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS4 and BBS5 also interact directly and coordinate the ciliary removal of polycystin 2. Hence, we reveal a novel and highly conserved role for the BBSome in fine-tuning ciliary signaling by regulating the ciliary removal of sensory receptors for lysosomal degradation.

No MeSH data available.


Related in: MedlinePlus