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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

The BBSome regulates the removal of ciliary receptors for lysosomal degradation but not proteasomal degradation.(a, b) Treating with lysosomal inhibitor Chloroquine, but not proteasome inhibitor MG132, caused ~2 fold increasing for the ciliary level of PC2 in RPE cells. Anti-Acetylated tubulin (Ac-tub) antibody was used to label cilia. DNA was stained with DAPI. Scale bar, 5 μm. Data represent three or more experiments. Bars in red indicate mean ± SEM. ***p < 0.001. n > 40. (c, d) Working model for the BBSome in regulating the degradative sorting of ciliary sensory receptors.
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f7: The BBSome regulates the removal of ciliary receptors for lysosomal degradation but not proteasomal degradation.(a, b) Treating with lysosomal inhibitor Chloroquine, but not proteasome inhibitor MG132, caused ~2 fold increasing for the ciliary level of PC2 in RPE cells. Anti-Acetylated tubulin (Ac-tub) antibody was used to label cilia. DNA was stained with DAPI. Scale bar, 5 μm. Data represent three or more experiments. Bars in red indicate mean ± SEM. ***p < 0.001. n > 40. (c, d) Working model for the BBSome in regulating the degradative sorting of ciliary sensory receptors.

Mentions: Intriguingly, mammalian BBS4 has been implicated in regulating the proteasomal degradation of signaling mediators at cilia base45. To examine whether the ciliary accumulation of PC2 in BBSome-deficient RPE cells is caused by defective lysosomal degradation or proteasomal degradation, we treated the cells with the lysosomal inhibitor chloroquine or the proteasomal inhibitor MG132 at physiological relevant concentrations. Treatment of RPE cells with chloroquine, but not MG132, significantly increased cilia surface localization of PC2 protein by 2-fold (Fig. 7a,7b). Total protein level for PC2 was not altered after treating with chloroquine or MG132 (data not shown). We thus concluded that disrupted lysosomal degradation but not proteasomal degradation leads to the ciliary accumulation of PC2 similar to that observed in BBSome-deficient cells. In summary, these results suggest a redundant and conserved role for BBS4 and BBS5 in the BBSome in downregulating cilia receptors for lysosomal degradation (Fig. 7c,d).


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)

The BBSome regulates the removal of ciliary receptors for lysosomal degradation but not proteasomal degradation.(a, b) Treating with lysosomal inhibitor Chloroquine, but not proteasome inhibitor MG132, caused ~2 fold increasing for the ciliary level of PC2 in RPE cells. Anti-Acetylated tubulin (Ac-tub) antibody was used to label cilia. DNA was stained with DAPI. Scale bar, 5 μm. Data represent three or more experiments. Bars in red indicate mean ± SEM. ***p < 0.001. n > 40. (c, d) Working model for the BBSome in regulating the degradative sorting of ciliary sensory receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: The BBSome regulates the removal of ciliary receptors for lysosomal degradation but not proteasomal degradation.(a, b) Treating with lysosomal inhibitor Chloroquine, but not proteasome inhibitor MG132, caused ~2 fold increasing for the ciliary level of PC2 in RPE cells. Anti-Acetylated tubulin (Ac-tub) antibody was used to label cilia. DNA was stained with DAPI. Scale bar, 5 μm. Data represent three or more experiments. Bars in red indicate mean ± SEM. ***p < 0.001. n > 40. (c, d) Working model for the BBSome in regulating the degradative sorting of ciliary sensory receptors.
Mentions: Intriguingly, mammalian BBS4 has been implicated in regulating the proteasomal degradation of signaling mediators at cilia base45. To examine whether the ciliary accumulation of PC2 in BBSome-deficient RPE cells is caused by defective lysosomal degradation or proteasomal degradation, we treated the cells with the lysosomal inhibitor chloroquine or the proteasomal inhibitor MG132 at physiological relevant concentrations. Treatment of RPE cells with chloroquine, but not MG132, significantly increased cilia surface localization of PC2 protein by 2-fold (Fig. 7a,7b). Total protein level for PC2 was not altered after treating with chloroquine or MG132 (data not shown). We thus concluded that disrupted lysosomal degradation but not proteasomal degradation leads to the ciliary accumulation of PC2 similar to that observed in BBSome-deficient cells. In summary, these results suggest a redundant and conserved role for BBS4 and BBS5 in the BBSome in downregulating cilia receptors for lysosomal degradation (Fig. 7c,d).

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