BBSome

A BBSome is a protein complex that operates in primary cilia biogenesis, homeostasis, and intraflagellar transport (IFT). The BBSome recognizes cargo proteins and signaling molecules like G-protein coupled receptors (GPCRs) on the ciliary membrane and helps transport them to and from the primary cilia. Primary cilia are nonmotile microtubule projections that function like antennae and are found in many types of cells. They receive various environmental signals to aid the cell in survival. They can detect photons by concentrating rhodopsin, a light receptor that converts photons into chemical signals, or odorants by concentrating olfactory receptors on the primary cilia surface. Primary cilia are also meaningful in cell development and signaling. They do not contain any way to make proteins within the primary cilia, so the BBSome aids in transporting essential proteins to, from, and within the cilia. Examples of cargo proteins that the BBSome is responsible for ferrying include smoothened (a component of the Hedgehog signaling pathway), polycystic-1 (PC1), and several G-Protein coupled receptors (GPCRs) like somatostatin receptors (Sstr3), melanin-concentrating hormone receptor 1 (Mchr1), and neuropeptide Y2 receptor.

The BBSome is an eight-protein complex consisting of different subunits named Bardet-Biedl Syndrome (BBS) proteins after the ciliopathy disease caused by a mutation in BBS proteins. Currently, there are 24 discovered BBS gene products that either form the BBSome or interact with the BBSome. Several BBS proteins that are not associated with the BBSome (BBS11, BBS13, BBS15, BBS16, BBS19-24) have yet to be extensively studied. The proteins within the largest and most stable BBSome core complex are BBS1, BBS4, BBS5, BBS8, BBS9, and BBS-interacting protein BBIP1, also known as BBS18. BBIP1 is the proposed eighteenth BBS gene due to its essential role in interacting with the BBSome and reduced levels in patients with a BBS diagnosis. BBS2 and BBS7 are also within the BBSome but are more loosely associated, which leads to their exclusion in the core complex. Other BBSome-associated proteins can be found in higher-level organisms with more IFT requirements. For example, BBS6, BBS10, and BB12 form into chaperonin complexes with CCT/TRiC (chaperonin-containing tailless complex polypeptide 1/tailless complex polypeptide 1 ring complex) in chordates which function to regulate and oversee the assembly of the BBSome in an ATP-dependent manner. BBS3 associates with Arl6 (ARF-like 6) and helps in recruiting the BBSome to ciliary membranes. BBS7 interacts with LZTFL1 (Leucine Zipper Transaction Factor-Like 1) to regulate the entry of the BBSome into the primary cilia. The BBSome has a similar structure and function compared to COPI, COPII, and clathrin coats showing its similarity to the function of these vesicle-forming complexes in transporting proteins. All BBS proteins are highly conserved in genetics which shows their importance in primary cilium biogenesis and intraflagellar transport (IFT).

The BBSome links cargo proteins to intraflagellar transport (IFT) machinery, which transports structural components and receptors, with the help of motor proteins dynein and kinesin, from the tip to the base of the primary cilia (anterograde transport) and back (retrograde transport) along ciliary microtubules. Since cilia cannot synthesize proteins, the IFT pathway is required for biogenesis, maintenance, and signaling within the cilia through motors, IFT-A and IFT-B subcomplexes, and the cargo proteins. The BBSome assists with the assembly and stabilization of the IFT complex at the ciliary base and mediates the bidirectional movement, all of which sustains the success of IFT. IFT-A controls retrograde IFT, and IFT-B controls anterograde transport. DYF-2 is a protein that functions with BBS1 to stabilize the interaction between the BBSome and the IFT complex in preparation for retrograde transport. In mutants with nonfunctional BBSome proteins, IFT-B can not associate with IFT-A, which demonstrates the BBSome function of assembling the IFT machinery. An experiment performed with Caenorhabditis elegans looked at GFP-tagged IFT-B protein complexes to look for IFT-B accumulation at the tip of the primary cilia in organisms with inhibited IFT turnaround. The defective (Dyf) C. elegans mutants showed a dissociation between the BBSome and IFT particles causing BBS proteins to accumulate at the ciliary base, regular anterograde transport, but an accumulation of IFT-B components at the ciliary tip due to an absence of the BBSome.

BBS gene expression has been observed in nonciliated cells in cardiac, vascular, and renal tissues, which expands the parameters of the BBSome functions to cellular processes other than solely primary cilia protein transport, such as plasma membrane receptor localization, gene expression, and cell division. The discovery that BBS7, and other BBS proteins, like BBS4, enter the nucleus and, in the case of BBS7, interact with ring finger protein 2 (RNF2) to regulate its transcription supports the concept that the BBSome might also be involved in gene expression. It is not yet definitive on whether this gene expression role is separate from the BBSome transportation of proteins function.