BBSome

[1] 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.

[10] All BBS proteins are highly conserved in genetics which shows their importance in primary cilium biogenesis and intraflagellar transport (IFT).

[12] 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.

[7] It was discovered by Maxence Nachury, Alexander Loktev, and several other associates in a study performed in 2007 that used biochemical purification of complexes that contained BBS4 in mammalian cells.

[4] They hypothesized that the BBSome was transported to the basal body by centriolar satellites, which are cytoplasmic granules that bring specific proteins to the centrosome due to its connection to PCM-1.

[4] They also discovered the relationship between the subunits of interactions of BBS1/BBS2/BBS7 with β-propeller domains, BBS4/BBS8 with TPR (tetratricopeptide repeat) regions, BBS3/Arl6, and BBS6/BBS10/BBS12 relations for chaperonin-like functions.

[14] High-resolution cryo-electron microscopy with an average of 3.8 Å was used to display the overall complex structure, but it did not allow for an accurate atomic model due to limited resolution.

that the BBSome assembles sequentially, beginning with the association of BBS7, BBS chaperonins, and the CCT/TRiC complex, which functions as a scaffold to which further subunits can bind.

[17][18] The necessity of having a properly assembled BBSome highlights the importance of the interactions between the subunits to the function of the protein complex.

BBS5 has two pleckstrin homology (PH) domains that can bind to phosphoinositides, mainly phosphatidylinositol 3-phosphate (PI3P) and phosphatidic acid (PA), which are thought to be essential for cilia biogenesis.

[25] The BBSome, specifically the interaction between the BBS1 subunit and the C-terminus of Rabin8, is thought to aid with the GEF activity of Rabin8 to direct vesicles leaving the Golgi Body to the base of the cilia.

[25] BBSome activity has recently been expanded to systems other than primary cilia transports and has been connected to renal, neuronal, vascular, and cardiac development, regulation, and function.

[29][30] Bardet-Biedl Syndrome is an autosomal recessive disorder that occurs in about 1 in every 100,000 live births and is due to homozygous mutations in any of the BBS genes other than BBIP1.

[6] Exons of their DNA samples were acquired, underwent high throughput sequencing, were aligned with the human reference genome, and single nucleotide polymorphism calling was performed.

[7] This system of leptin expression and regulation is a BBSome pathway that is independent of cilia, showing the diverse and greatly unknown applications for the complex.

A study performed with mice that had a nonfunctional BBSome were found to be incapable of transducing leptin signals in certain hypothalamic neurons.

[4][2] The mice used in this experiment gained weight over the course of the study due to the lack of leptin receptors that could be transported to the cilia for environment signaling.

[40][38][41][42] The renal anomalies that can arise due to BBS deficiencies can cause serious medical problems that may lead to dialysis or kidney transplantation.

A study with knockout Bbs4 gene in mice resulted in decreased urine production and increased sodium and blood urea nitrogen concentrations leading to the development of glomerular cysts.

[26] The BBSome has also been connected to cardiac development and maintenance, with particular function in the renin-angiotensin system, due to its high prevalence in people with BBS.

[7][4] Different defects that have been explored in connection with the BBSome are dilated cardiomyopathy, aortic valve stenosis, and hypertrophy of the interventricular septum.

[44] Studies involving mice with BBS gene deletions have shown that mutations or defects in the BBSome activity can lead to cardiovascular issues like hypertension.

[46] A study was performed using a mouse model to analyze the effects of BBSome activity dysfunction in smooth muscle cells through the deletion of the Bbs1 gene on vascular function, blood pressure, and arterial stiffening.

[28] The higher SNA and increased body weight due to the deletion of BBS genes all contributed to the development of hypertension in the mice.

[7] Even people without the BBSome dysfunction causing ciliopathy Bardert-Biedl Syndrome have been found to have certain symptoms of the disease such as obesity or hypertension due to variance or small mutations in some of the BBS genes.

A study on the importance between Rab8-GTP production to BBS was performed when scientists injected mRNAs coding for Rab8 mutations into one-cell zebrafish embryos.

[25] These mutations end in abnormalities in Kupffer's vesicle which is analogous to the node in humans and contributes to the inversion of organ laterality.

[51] The nonfunctional BBSome leads to defects in the primary cilia that covers Kupffer's vesicle, a complex that is responsible for instituting left and right asymmetry of the brain, heart, and gut in zebrafish during embryonic development.

[52] The lack of BBSome functionality also caused delays in dynein-dependent retrograde transport of melanosomes, organelles that synthesize and contain melanin.

[12] When bbs4 mutants of Chlamydomonas were analyzed, researchers found that the cells showed normal flagellar structure, but had defective IFT transport.

( A–E ) The described order of addition of subunits has been chosen for visual clarity and does not reflect the sequential assembly in vivo. BBS4 and BBS8 are shown in two different views to visualize the superhelical arrangement of the TPR repeats. Likewise, domains of BBS1 and BBS9 are also shown individually in two views. [ 16 ]
( A ) Domain architecture of the protomers forming the BBSome core complex. The parts of the primary structure that could be assigned in the density is shown in full colors, while non-modeled regions are represented in opaque colors. ( B ) Composite cryo-EM density map of the BBSome core complex in different orientations. Each protomer is colored differently and the thresholds of the segmented densities of the individual domains were adjusted to visualize each domain at an optimal signal intensity. BBS5 is poorly visible at the signal level of the other subunits and required a reconstruction from a subset of particles, which was obtained by 3D-sorting (Figure 1—figure supplement 1). ( C ) The final model of the core BBSome. ( D ): Schematic representation of the complex, highlighting the two β-propeller domains of BBS1 and BBS9 as red and green segmented wheels, and the super helical arrangements of the TPR repeats of BBS4 and BBS8 as blue and cyan helices. [ 1 ]
The assembly of the 8 units of the BBSome is mediated by the BBScc (Bardet-Biedl syndrome [BBS] chaperonins complex) that contains BBS6, BBS10, and BBS12. A major role of the BBSome relates to the trafficking of cargos to and from cilia including G protein–coupled receptors through a process that involves BBS3. The BBSome has also emerged as a critical mechanism for the cell membrane localization of various receptors including the leptin receptor, insulin receptor, and G protein–coupled receptors in a manner independent of its ciliary function. In addition, the BBSome has been implicated in the regulation of several other cellular processes including cytoskeleton dynamic, RhoA (rat sarcoma virus homolog family member A) activity, proteasomal activity, and gene expression. The dashed line indicates a potential, but not proven, function of the BBSome. [ 22 ]
Depiction of the cardiovascular effects evoked by deficiency in the BBSome and related proteins in keys organs (brain, kidney, heart, and vasculature) involved in the control of various cardiovascular parameters. [ 22 ]