3.A.33. The BBSome Complex (BBSome) Family
The BBSome complex is thought to function as a coat complex required for sorting specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. It is required for primary cilia assembly and BBSome stability by transporting proteins. It regulates cytoplasmic microtubule stability and acetylation and is involved in ciliary biogenesis and degradation. It is involved in BBSome-mediated cargo-targeting to the eukaryotic cilium and has been reviewed (Zhao and Rahmouni 2022; Wingfield et al. 2018). RABL4/IFT27, in a nucleotide-independent manner, promotes phospholipase D ciliary retrieval by facilitating BBSome reassembly at the ciliary tip (Liu et al. 2023).
Retinal degeneration due to photoreceptor ciliary-related proteins dysfunction accounts for more than 25% of all inherited retinal dystrophies. Taking the Bardet-Biedl syndrome (BBS) as an emblematic example as well as other related syndromic ciliopathies, the contribution of a wide range of models has enabled to characterize the role of the BBS proteins in the archetypical cilium but also at the level of the connecting cilium of the photoreceptors. There are more than 24 BBS genes coding for proteins that form different complexes such as the BBSome and the chaperone protein complex. Many BBS proteins (but not the chaperonins) can be modeled in primitive organisms such as Paramecium, Chlamydomonas reinardtii, Trypanosoma brucei, and Caenorhabditis elegans. Assessing the role of the primary cilial structure of the connecting cilium of the photoreceptor cells has been studied by way of zebrafish modeling (Danio rerio) as well as by mouse models. Human cell models can now be used notably thanks to gene editing and the use of induced pluripotent stem cells (iPSCs). All these models are not only important for pathogenesis understanding but also very useful for studying therapeutic avenues, their pros and cons, especially for gene replacement therapy as well as pharmacological triggers (Delvallée and Dollfus 2023; Lechtreck 2022).
Certain ciliary transmembrane and membrane-tethered signaling proteins migrate from the ciliary tip to the base via retrograde intraflagellar transport (IFT), essential for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. During this process, the BBSome functions as an adaptor between retrograde IFT trains and these signaling protein cargoes. The Arf-like 13 (ARL13) small GTPase resembles ARL6/BBS3 in facilitating these signaling cargoes to couple with the BBSome at the ciliary tip prior to loading onto retrograde IFT trains for transporting towards the ciliary base (Liu et al. 2023). Chlamydomonas ARL13 only in a GTP-bound form (ARL13(GTP)) anchors to the membrane for diffusing into cilia. Upon entering cilia, ARL13 undergoes a GTPase cycle for shuttling between the ciliary membrane (ARL13(GTP)) and matrix (ARL13(GDP)). To achieve this goal, the ciliary membrane-anchored BBS3(GTP) binds the ciliary matrix-residing ARL13(GDP) to activate the latter as an ARL13 guanine nucleotide exchange factor. At the ciliary tip, ARL13(GTP) recruits the ciliary matrix-residing and post-remodeled BBSome as an ARL13 effector to anchor to the ciliary membrane. This makes the BBSome spatiotemporally become available for the ciliary membrane-tethered phospholipase D (PLD) to couple with. Afterward, ARL13(GTP) hydrolyzes GTP for releasing the PLD-laden BBSome to load onto retrograde IFT trains. According to this model, hedgehog signaling defects associated with ARL13b and BBS3 mutations in humans could be satisfactorily explained, providing us a mechanistic understanding behind BBSome-cargo coupling required for proper ciliary signaling (Liu et al. 2023).