Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond

  1. Xiaoyu Tian  Is a corresponding author
  2. Huijie Zhao
  3. Jun Zhou  Is a corresponding author
  1. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, China
  2. State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, China
6 figures and 1 table


Sequential assembly model of the BBSome.

The CCT chaperonin complex and BBS6/10/12 stabilize BBS7 to form the BBS-chaperonin complex, which recruits BBS2 for BBS7 binding. BBS2 directly interacts with BBS9 and BBS7 to form a ternary core complex before subsequent recruitment of other BBSome subunits. BBS4, which localizes on the centriolar satellites, is presumably the last subunit to be incorporated into the BBSome, whereas the basal body-localized BBS1 facilitates transfer of the BBSome into the cilium. BBSome transfer from centriolar satellites to the basal body (and then to the cilium) is regulated by centriolar satellite proteins (e.g. CEP72, CEP290, SSX2IP, CCDC66, DZIP1, and AZI1).

Domain organization of homo BBSome subunits.

The number of residues and the domain structures are indicated. α, alpha helices; GAE, gamma-adaptin ear domain; cc, coiled-coil domain; PF, platform domain; PH, pleckstrin-homology domain.

Structure of the mammalian BBSome.

(A) Atomic models of the eight subunits of the bovine BBSome. (B) Cryo-EM structure of the bovine BBSome. (C) Cryo-EM structure of the BBSome:ARL6:GTP complex in the same orientations as the map in panel B. Images are adapted from Singh et al., 2020, where it was published under a CC BY 4.0 license.

Non-ciliary functions of the BBSome.

The BBSome is involved in a wide range of cellular functions including intracellular vesicular transport, cytoskeletal dynamics, gene expression, and cellular and organelle homeostasis. ER, endoplasmic reticulum; UPR, unfolding protein response.

Ciliary transport of the BBSome.

(A) The BBSome is recruited to the basal body through ARL6-GTP and IFT22-GTP. LZTFL1 also facilitates basal body recruitment of the BBSome. At the ciliary tip, IFT25/27 promotes BBSome reassembly for retrograde transport. At the proximal ciliary region above the transition zone, a portion of cargo-laden BBSome sheds off retrograde IFT and acts as the effector of ARL3 for ciliary retrieval. (B) The BBSome is recruited to the membrane as an effector of ARL6-GTP. Ciliary entry of the BBSome is facilitated by IFT-A and transition zone proteins NPHP5 and CEP290. (C) The BBSome rides on the retrograde transport train, probably mediated by the IFT-B components IFT27 and IFT25. Whether the adaptor protein LZTFL1 functions as the linker between the BBSome and IFT-B remains to be demonstrated (D) At the ciliary tip, IFT27 disassociates from IFT-B to activate ARL6. Then, ARL6-GTP arranges the BBSome onto the membranes for retrograde transport. (E) During ciliary exit, the BBSome is transported across the transition zone on IFT-B, where Rabl2-GTP hydrolyses to the Rabl2-GDP form to dissociate from IFT trains. The BBSome sheds off from the IFT-B trains and fails to pass through the transition zone when the IFT-B is persistently bound by the GTP-locked Rabl2.

Functions of the BBSome in the cilium.

(A) The anchoring of the BBSome on IFT trains. The BBSome interacts with IFT-B through IFT38. The Rabl2 GTPase and the IFT25-IFT27 dimer bind to IFT74-IFT81 of IFT-B in a mutually exclusive manner and may regulate BBSome-mediated cargo loading. (B) During the cargo’s ciliary entry, the BBSome either regulates vesicle targeting in a Rab8-Rabin8-dependent manner or regulates the cargo’s lateral transport between the plasma and ciliary membrane. At the ciliary base and at the ciliary tip, the BBSome may regulate IFT assembly to ensure their ciliary entry and turnaround and hold them together during transport. At the ciliary tip, ARL6 and ARL13 regulate cargo pickup by the BBSome for retrieval. During the cargo’s exit, β-arrestin arranges the cargo for ubiquitin modification, followed by BBSome-mediated exit across the transition zone. TOM1L2 may function as an adapter between the BBSome and ubiquitin sidechains. The BBSome facilitates endocytic sorting of select membrane proteins at the base of the cilium. The unretrieved GPCRs can also be shed into ectocytosis vesicles for disposal.


Table 1
Characteristics and functions of BBS genes.
NoGene SymbolGene NameProteinFunctionsReferences
1BBS1Bardet-Biedl syndrome 1Bardet-Biedl syndrome 1 proteinMember of the BBSome complexMykytyn et al., 2002
2BBS2Bardet-Biedl syndrome 2Bardet-Biedl syndrome 2 proteinMember of the BBSome complexNishimura et al., 2001
3ARL6ADP ribosylation factor like GTPase 6ADP-ribosylation factor-like protein 6Small GTPase; Facilitate BBSome assembly and recruitment to the ciliumChiang et al., 2004; Fan et al., 2004
4BBS4Bardet-Biedl syndrome 4Bardet-Biedl syndrome 4 proteinMember of the BBSome complexMykytyn et al., 2001
5BBS5Bardet-Biedl syndrome 5Bardet-Biedl syndrome 5 proteinMember of the BBSome complexWoods et al., 1999; Young et al., 1999
6MKKSMKKS centrosomal shuttling proteinMcKusick-Kaufman/Bardet-Biedl syndromes putative chaperoninChaperonin protein for BBSome complex assemblyKatsanis et al., 2000; Slavotinek et al., 2000
7BBS7Bardet-Biedl syndrome 7Bardet-Biedl syndrome 7 proteinMember of the BBSome complexBadano et al., 2003a
8TTC8Tetratricopeptide repeat domain 8Tetratricopeptide repeat protein 8Member of the BBSome complexAnsley et al., 2003
9BBS9Bardet-Biedl syndrome 9Protein PTHB1Member of the BBSome complexNishimura et al., 2005
10BBS10Bardet-Biedl syndrome 10Bardet-Biedl syndrome 10 proteinChaperonin protein for BBSome complex assemblyStoetzel et al., 2006
11TRIM32Tripartite motif containing 32E3 ubiquitin protein ligase TRIM32E3 ubiquitin ligaseChiang et al., 2006
12BBS12Bardet-Biedl syndrome 12Bardet-Biedl syndrome 12 proteinChaperonin protein for BBSome complex assemblyStoetzel et al., 2007
13MKS1MKS transition zone complex subunit 1Meckel syndrome type 1 proteinTransition zone component; Regulates ciliary traffickingLeitch et al., 2008
14CEP290Centrosomal protein 290Centrosomal protein of 290 kDa (Cep290)Transition zone component; Regulates ciliary entryLeitch et al., 2008
15WDPCPWD repeat containing planar cell polarity effectorWD repeat containing and planar cell polarity effector protein fritz homolog (hFRTZ)Component of the CPLANE (ciliogenesis and planar polarity effectors) complex; regulates ciliogenesisKim et al., 2010
16SDCCAG8SHH signaling and ciliogenesis regulator SDCCAG8Serologically defined colon cancer antigen 8Regulates ciliogenesis and Hedgehog signaling pathwayOtto et al., 2010
17LZTFL1Leucine zipper transcription factor like 1Leucine zipper transcription factor-like protein 1Regulates the BBSome traffickingMarion et al., 2012b
18BBIP1BBSome interacting protein 1BBSome-interacting protein 1Member of the BBSome complexLoktev et al., 2008
19IFT27Intraflagellar transport 27Intraflagellar transport protein 27 homologIFT-B complex component; Required for ciliary traffickingAldahmesh et al., 2014
20IFT172Intraflagellar transport 172Intraflagellar transport protein 172 homologIFT-B complex componentBujakowska et al., 2015
21CFAP418Cilia And Flagella Associated Protein 418Cilia- and flagella-associated protein 418A ciliary protein of unknown functionKhan et al., 2016; Heon et al., 2016
22IFT74Intraflagellar transport 74Intraflagellar transport protein 74 homologIFT-B complex componentLindstrand et al., 2016
23NPHP1Nephrocystin 1Nephrocystin-1Transition zone componentLindstrand et al., 2014
24SCAPERS-phase cyclin A associated protein in the ERS phase cyclin A-associated protein in the endoplasmic reticulum (S phase cyclin A-associated protein in the ER)Regulates ciliary dynamicsWormser et al., 2019
25CCDC28BCoiled-coil domain containing 28BCoiled-coil domain-containing protein 28BCentrosomal protein that regulates ciliogenesisBadano et al., 2006
26SCLT1Sodium channel and clathrin linker 1Sodium channel and clathrin linker 1Distal appendage component that regulates ciliogenesisMorisada et al., 2020

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiaoyu Tian
  2. Huijie Zhao
  3. Jun Zhou
Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond
eLife 12:e87623.