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<inf>-4</inf> and BBS<inf>-5</inf>, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS<inf>-4</inf> directly interacts with BBS<inf>-5</inf> and the interaction can be disrupted by a conserved mutation identified in human BBS<inf>4</inf>. Surprisingly, we found that BBS<inf>-4</inf> and BBS<inf>-5</inf> 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<inf>-4</inf> and BBS<inf>-5</inf> disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS<inf>4</inf> and BBS<inf>5</inf> 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.
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