BBIP1 (also known as BBIP10 and BBS18) is the small (92 aa, ~10.5 kDa) eighth core subunit of the BBSome, an octameric, coat-like adaptor complex (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10) that traffics signaling membrane receptors, including ciliary GPCRs, into and out of the primary cilium in conjunction with intraflagellar transport and the small GTPase ARL6/BBS3. BBIP1 is an integral, stably incorporated subunit that joins the complex through BBS4 and is required for BBSome integrity/stability and for primary cilium assembly. It is found inside the primary cilium and in the cytoplasm but not at centriolar satellites. Beyond its structural role in the BBSome, BBIP1 has a distinct activity not shared by other BBSome subunits; it is required for cytoplasmic microtubule polymerization and acetylation, acting in part through physical interaction with the tubulin deacetylase HDAC6. BBIP1 is restricted to ciliated organisms, and loss-of-function mutations cause the ciliopathy Bardet-Biedl syndrome type 18.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0034464
BBSome
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: BBIP1/BBIP10 is a bona fide, experimentally validated core subunit of the BBSome. The phylogenetic (IBA) call agrees with direct experimental evidence.
Reason: BBIP10 was discovered and characterized as the eighth BBSome subunit and is an integral component that binds the complex through BBS4. This is a core cellular-component annotation for the gene.
|
|
GO:0097500
receptor localization to non-motile cilium
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The BBSome's central, defining function is trafficking signaling receptors (e.g. ciliary GPCRs) into and out of the primary (non-motile) cilium. As an integral subunit required for BBSome integrity, BBIP1 is appropriately annotated to this process.
Reason: Term definition (a receptor is transported to, or maintained in, a location within a non-motile cilium) matches the established BBSome cargo- trafficking role; this is a core biological process for the gene.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: UniProt records BBIP1 in the cytoplasm, consistent with its cytoplasmic microtubule role and with BBSome subunits cycling through the cytoplasm before ciliary entry. This IEA call is corroborated by the experimental IDA below.
Reason: Correct but generic localization; the informative CC annotations are BBSome, cilium, and ciliary membrane. Retain as supporting context.
|
|
GO:0005929
cilium
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: BBIP1 localizes inside the primary cilium, like other BBSome subunits. The UniProt subcellular-location-derived IEA is consistent with experimental data.
Reason: Ciliary localization is well supported experimentally and is central to BBIP1/BBSome function.
|
|
GO:0034464
BBSome
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro2GO (IPR028233, BBIP10 family) maps the BBSome membership. This is redundant with, and corroborated by, the experimental BBSome annotations.
Reason: Family-level electronic inference correctly assigns BBSome membership, consistent with direct evidence.
|
|
GO:0060271
cilium assembly
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: BBIP1 is required for primary cilium assembly; the InterPro2GO electronic inference agrees with the experimental IMP from the same depletion study.
Reason: Cilium assembly is a core, experimentally supported process for BBIP1; the IEA is corroborated.
|
|
GO:0005515
protein binding
|
IPI
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
MARK AS OVER ANNOTATED |
Summary: This IPI (WITH BBS4/Q96RK4) records a real, meaningful interaction (BBIP10 binds the BBSome through BBS4), but the term "protein binding" is uninformative and discouraged. The biological meaning is captured by the BBSome part_of annotations and, separately, by the HDAC6 interaction.
Reason: GO:0005515 conveys no specific function; the underlying BBS4 interaction is already represented by BBSome membership. Per curation guidance, avoid bare protein binding.
|
|
GO:0005515
protein binding
|
IPI
PMID:22500027 Intrinsic protein-protein interaction-mediated and chaperoni... |
MARK AS OVER ANNOTATED |
Summary: Same uninformative term, supported by the BBSome assembly study showing BBIP10 binds the complex via BBS4. Better represented as BBSome membership.
Reason: Protein binding is not an informative molecular function; the specific interaction is captured by the BBSome part_of annotations.
|
|
GO:0005515
protein binding
|
IPI
PMID:29039417 Protein interaction perturbation profiling at amino-acid res... |
MARK AS OVER ANNOTATED |
Summary: High-throughput Y2H perturbation profiling across the eight BBSome subunits (WITH BBS4/Q96RK4). Confirms BBIP1 PPIs within the BBSome but yields only the generic protein-binding term.
Reason: Uninformative MF term; the meaningful content (BBSome subunit interactions) is captured by BBSome membership annotations.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5617815 |
KEEP AS NON CORE |
Summary: Reactome places the BBSome (and thus BBIP1) in the cytosol during pathway steps prior to ciliary entry. Consistent with cytoplasmic localization but less specific than the BBSome/ciliary CCs.
Reason: Plausible and curator-asserted (TAS), but generic; the informative localizations are BBSome, cilium, ciliary membrane.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5624125 |
KEEP AS NON CORE |
Summary: Duplicate cytosol localization from the Reactome Formation of the BBSome reaction.
Reason: Correct but generic localization; retain as supporting, non-core.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5624126 |
KEEP AS NON CORE |
Summary: Duplicate cytosol localization from a Reactome BBSome cargo-binding reaction.
Reason: Correct but generic localization; retain as supporting, non-core.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5624127 |
KEEP AS NON CORE |
Summary: Duplicate cytosol localization from a Reactome BBSome cargo-targeting reaction.
Reason: Correct but generic localization; retain as supporting, non-core.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5624129 |
KEEP AS NON CORE |
Summary: Duplicate cytosol localization from the Reactome LZTFL1-BBSome reaction.
Reason: Correct but generic localization; retain as supporting, non-core.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
KEEP AS NON CORE |
Summary: HPA immunofluorescence places BBIP1 in the cytosol. Consistent with cytoplasmic localization and the cytoplasmic microtubule role, though generic.
Reason: Experimentally observed but non-specific localization; informative CCs are BBSome, cilium, ciliary membrane.
|
|
GO:0036064
ciliary basal body
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: HPA immunofluorescence localizes BBIP1 to the ciliary basal body. The BBSome traffics through the basal body en route to the cilium, so this is plausible. Note UniProt states BBIP1 localizes inside the cilium but NOT at centriolar satellites; basal body is distinct from satellites.
Reason: Experimental (IDA) localization consistent with the BBSome trafficking route through the basal body; defer to the experimental call.
Supporting Evidence:
file:human/BBIP1/BBIP1-deep-research-falcon.md
is present along the ciliary axoneme but not at centriolar satellites
|
|
GO:0034464
BBSome
|
IPI
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
ACCEPT |
Summary: Direct experimental evidence (mass-spec identification of BBIP10 within the purified BBSome; ComplexPortal CPX-1908) establishes BBIP1 as a BBSome subunit. This is the strongest CC annotation.
Reason: Core, experimentally validated cellular-component annotation; defining identity of the gene product.
|
|
GO:0060170
ciliary membrane
|
IDA
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
ACCEPT |
Summary: The BBSome acts as a membrane coat at the ciliary membrane and BBIP10 localizes within the cilium. ComplexPortal IDA annotation to ciliary membrane reflects where the complex functions.
Reason: Consistent with the BBSome coat function at the ciliary membrane and with BBIP1's ciliary localization; experimentally supported.
|
|
GO:0060271
cilium assembly
|
NAS
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
ACCEPT |
Summary: Non-traceable author statement of the cilium-assembly role from the discovery paper. The same process is independently supported by the IMP annotation below.
Reason: Correct process; redundant with stronger IMP evidence from the same study.
|
|
GO:0005737
cytoplasm
|
IDA
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
KEEP AS NON CORE |
Summary: Direct experimental observation of cytoplasmic BBIP1, consistent with UniProt subcellular location and with its cytoplasmic microtubule function.
Reason: Experimentally observed but generic localization; informative CCs are BBSome, cilium, ciliary membrane.
|
|
GO:0034464
BBSome
|
IDA
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
ACCEPT |
Summary: Direct experimental evidence (UniProt-curated IDA) that BBIP10 is part of the BBSome.
Reason: Core, experimentally validated BBSome membership; defining function.
|
|
GO:0060271
cilium assembly
|
IMP
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
ACCEPT |
Summary: BBIP10 depletion impairs ciliogenesis (characteristic BBS phenotypes in zebrafish; ciliary defects in cells). Strong mutant-phenotype evidence for a role in cilium assembly.
Reason: Experimental IMP for a core biological process; the gene is required for primary cilium assembly.
|
|
GO:0005198
structural molecule activity
|
IDA
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
NEW |
Summary: Proposed new molecular-function annotation. BBIP1 is an integral structural subunit that contributes to BBSome integrity/stability; this captures its subunit-level structural role, which is currently only implied by the generic protein-binding IPIs. The falcon deep research summarizes the subunit-specific assembly requirement, noting that BBIP1 depletion prevents BBSome assembly and causes BBS4 to fail to copurify with the other subunits.
Reason: Captures BBIP1's structural contribution to the BBSome (required for BBSome stability), a more informative molecular function than protein binding. This is genuinely subunit-specific (a depletion phenotype of BBIP1 itself), not merely inferred from holo-complex function.
Proposed replacements:
structural molecule activity
Supporting Evidence:
file:human/BBIP1/BBIP1-deep-research-falcon.md
Depletion of BBIP1 by siRNA prevents the assembly of the BBSome, as demonstrated by metabolic labeling experiments showing that BBS4 fails to copurify with other BBSome subunits in BBIP1-depleted cells
|
|
GO:0046785
microtubule polymerization
|
IMP
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
NEW |
Summary: Proposed new biological-process annotation capturing BBIP1's distinct, non-BBSome-shared role in cytoplasmic microtubule polymerization and acetylation (rescued by HDAC6 inhibition; BBIP1 binds HDAC6). Not currently represented in GOA. The falcon deep research independently emphasizes that this microtubule-acetylation phenotype is specific to the BBIP1 subunit and is not seen on depletion of other BBSome subunits.
Reason: BBIP10 depletion abolishes cytoplasmic microtubule polymerization and acetylation, a function explicitly distinguished from its BBSome role.
Proposed replacements:
microtubule polymerization
Supporting Evidence:
file:human/BBIP1/BBIP1-deep-research-falcon.md
Depletion of BBIP1 results in marked reduction of cytoplasmic microtubule acetylation and dramatically decreased ciliogenesis, phenotypes not observed with depletion of other BBSome subunits
|
|
GO:0060090
molecular adaptor activity
|
IPI
PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... |
NEW |
Summary: Proposed new molecular-function annotation. BBIP1 physically interacts with the tubulin deacetylase HDAC6, and this interaction underlies its promotion of microtubule acetylation; an adaptor activity is a more informative MF than the generic protein-binding IPI from the same paper.
Reason: BBIP1 binds HDAC6 (with BBS4/Q96RK4) and couples the BBSome to tubulin acetylation; molecular adaptor activity captures this bridging role.
Proposed replacements:
molecular adaptor activity
Supporting Evidence:
file:human/BBIP1/BBIP1-deep-research-falcon.md
BBIP1 physically interacts with HDAC6, a tubulin deacetylase, and inhibition of HDAC6 restores microtubule acetylation in BBIP1-depleted cells
|
Q: Is the microtubule-stabilizing/acetylation function of BBIP1 mediated by BBSome-bound BBIP1 or by a free pool of BBIP1, and does it depend on direct HDAC6 inhibition versus an indirect mechanism?
Suggested experts: Maxence V. Nachury
Q: Does BBIP1 contribute specific structural contacts within the cryo-EM BBSome architecture that are required for cargo (GPCR) capture or membrane coating, beyond simply stabilizing the complex?
Experiment: Separation-of-function mutagenesis of BBIP1 to uncouple BBSome incorporation (BBS4 binding) from HDAC6 binding/microtubule acetylation, assayed by ciliary GPCR trafficking versus cytoplasmic microtubule acetylation in BBIP1-null cells.
Hypothesis: BBIP1's BBSome-structural role and its microtubule/HDAC6-related role are genetically separable functions of the same small protein.
Experiment: Map the BBIP1-HDAC6 interaction interface and test whether BBIP1 directly inhibits HDAC6 tubulin-deacetylase activity in vitro.
Hypothesis: BBIP1 promotes microtubule acetylation by directly antagonizing HDAC6 rather than by an indirect cellular mechanism.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
BBIP1 (UniProt: A8MTZ0), also known as BBIP10, BBS18, or NCRNA00081, encodes BBSome-interacting protein 1 in humans. The gene belongs to the BBIP10 family and contains the BBIP10 domain (IPR028233, PF14777) as specified in the UniProt annotation (scheidecker2014exomesequencingof pages 1-3, loktev2008abbsomesubunit pages 1-2, tian2023organizationfunctionsand pages 1-2). Literature searches confirm this is the correct protein with no ambiguities found.
BBIP1 is an essential structural component and the eighth subunit of the BBSome, an octameric protein complex composed of BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBIP1/BBS18 (loktev2008abbsomesubunit pages 1-2, tian2023organizationfunctionsand pages 1-2, jin2010theconservedbardetbiedl pages 1-2). Unlike enzymes or transporters, BBIP1 functions as an adapter/scaffold protein that is critical for BBSome assembly and stability.
BBIP1 plays an indispensable role in BBSome complex formation. Depletion of BBIP1 by siRNA prevents the assembly of the BBSome, as demonstrated by metabolic labeling experiments showing that BBS4 fails to copurify with other BBSome subunits in BBIP1-depleted cells (loktev2008abbsomesubunit pages 4-5). The initial characterization by Loktev et al. (2008) identified BBIP1 (originally named BBIP10 for "BBSome Interacting Protein of 10 kDa") as copurifying with the BBSome and cosedimenting with BBS4 at 14S in velocity sedimentation analysis (loktev2008abbsomesubunit pages 1-2). The protein strongly associates with the BBSome but does not bind to centriolar satellites where some BBSome subunits like BBS4 can also localize (loktev2008abbsomesubunit pages 3-4).
The sequential assembly model of the BBSome suggests that BBS-chaperonin complexes (BBS6, BBS10, BBS12, and CCT/TRiC proteins) first stabilize BBS7, which then interacts with BBS2 and BBS9 to form a core complex. Subsequently, BBS1, BBS5, BBS8, and BBS4 are added to complete the BBSome (zhang2012intrinsicproteinproteininteractionmediated pages 1-2). BBIP1 is integrated as a critical structural component, and its absence disrupts this assembly cascade (loktev2008abbsomesubunit pages 4-5).
The BBSome functions as a coat complex that recognizes and traffics membrane proteins to and from primary cilia (jin2010theconservedbardetbiedl pages 1-2, yang2020nearatomicstructuresof pages 1-2, singh2020structureandactivation pages 1-2). While BBIP1 does not possess a catalytic active site or transport substrates directly, it is essential for the BBSome's cargo adapter function. The BBSome recognizes ciliary targeting sequences (CTS) on transmembrane proteins, particularly G-protein-coupled receptors (GPCRs), and mediates their ciliary trafficking (jin2010theconservedbardetbiedl pages 1-2, wingfield2018traffickingofciliary pages 1-2, klink2020structureofthe pages 1-2).
Structural studies using cryo-electron microscopy have revealed that the BBSome adopts an autoinhibited closed conformation in solution and undergoes conformational changes upon binding to ARL6/BBS3-GTP, which recruits the complex to ciliary membranes (yang2020nearatomicstructuresof pages 1-2, singh2020structureandactivation pages 1-2). The activated BBSome forms a membrane-apposed coat that facilitates cargo recognition through a negatively charged cleft and multiple subunit interfaces (klink2020structureofthe pages 1-2). BBIP1 is necessary for maintaining the structural integrity required for these functional conformations.
BBIP1 localizes precisely to the primary cilium, where it colocalizes with other BBSome subunits such as BBS4 (loktev2008abbsomesubunit pages 1-2, loktev2008abbsomesubunit pages 3-4). Immunofluorescence studies in retinal pigmented epithelial (RPE) cells demonstrated that BBIP1 is present along the ciliary axoneme but not at centriolar satellites, distinguishing its localization pattern from BBS4 (loktev2008abbsomesubunit pages 3-4). The BBSome, including BBIP1, is enriched at the basal body and transition zone at the base of cilia (tian2023organizationfunctionsand pages 1-2, jin2009thebbsome pages 1-2).
BBIP1 requires the small GTPase ARL6/BBS3 for efficient ciliary localization. Depletion of ARL6 by siRNA prevents BBIP1 and other BBSome subunits from localizing to cilia (jin2010theconservedbardetbiedl pages 1-2). Once recruited to cilia, the BBSome cycles bidirectionally through the cilium via intraflagellar transport (IFT), with BBIP1 traveling as part of the complex along microtubule doublets (nakayama2018ciliaryproteintrafficking pages 1-2, wingfield2018traffickingofciliary pages 1-2, wei2012thebbsomecontrols pages 1-2).
BBIP1, as an integral BBSome component, participates in multiple ciliary signaling pathways by regulating the ciliary localization of signaling receptors rather than directly transducing signals.
The BBSome regulates Hedgehog (Hh) signaling by controlling the ciliary trafficking of key pathway components. Studies demonstrate that BBS proteins and the BBSome regulate the ciliary entry and exit of Smoothened (SMO), the primary Hh signal transducer, and GPR161, a negative regulator of the pathway (tian2023organizationfunctionsand pages 1-2, yang2020nearatomicstructuresof pages 1-2, seo2011anovelprotein pages 1-2). Depletion of BBSome components, including BBIP1, disrupts the proper redistribution of these receptors during pathway activation, leading to developmental defects such as polydactyly observed in Bardet-Biedl syndrome patients (tian2023organizationfunctionsand pages 2-3).
The BBSome functions primarily in the removal and export of ciliary GPCRs following receptor activation (wingfield2018traffickingofciliary pages 1-2). In BBS knockout mice lacking functional BBSome components, ciliary GPCRs including somatostatin receptor 3 (SSTR3), melanin-concentrating hormone receptor 1 (MCHR1), and neuropeptide Y receptor (NPY2R) fail to properly localize to or are retained in cilia (tian2023organizationfunctionsand pages 1-2, yang2020nearatomicstructuresof pages 1-2, tian2023organizationfunctionsand pages 2-3). The mislocalization of hypothalamic neuronal cilia GPCRs, particularly leptin receptor and MC4R pathway components, contributes to hyperphagia and obesity phenotypes in BBS (tian2023organizationfunctionsand pages 2-3).
The BBSome associates with IFT-A and IFT-B complexes and travels along ciliary microtubules powered by kinesin-2 (anterograde) and dynein-2 (retrograde) motors (nakayama2018ciliaryproteintrafficking pages 1-2, wingfield2018traffickingofciliary pages 1-2, wei2012thebbsomecontrols pages 1-2). The BBSome regulates IFT assembly at the ciliary base and IFT turnaround at the ciliary tip, with specific BBSome subunits playing roles in these processes (wei2012thebbsomecontrols pages 1-2). While not all organisms show identical BBSome-IFT dependencies, in mammalian cells the BBSome acts as an adapter linking membrane protein cargoes to the IFT machinery for ciliary transit (nakayama2018ciliaryproteintrafficking pages 1-2, wingfield2018traffickingofciliary pages 1-2).
The small GTPase ARL6 (also called BBS3) recruits the BBSome to ciliary membranes in its GTP-bound state (jin2010theconservedbardetbiedl pages 1-2, singh2020structureandactivation pages 1-2). ARL6-GTP recognizes a composite binding site formed by BBS1 and BBS7, and this interaction induces a conformational change in the BBSome that exposes cargo-binding sites and promotes coat polymerization (yang2020nearatomicstructuresof pages 1-2, singh2020structureandactivation pages 1-2). BBIP1 is required for the BBSome to respond to ARL6 activation, as BBIP1 depletion prevents BBSome assembly and thus eliminates the substrate for ARL6 recruitment.
BBIP1 has a distinctive function not shared by other BBSome subunits: regulation of cytoplasmic microtubule polymerization and acetylation (loktev2008abbsomesubunit pages 1-2, loktev2008abbsomesubunit pages 4-5). Depletion of BBIP1 results in marked reduction of cytoplasmic microtubule acetylation and dramatically decreased ciliogenesis, phenotypes not observed with depletion of other BBSome subunits (loktev2008abbsomesubunit pages 4-5). BBIP1 physically interacts with HDAC6, a tubulin deacetylase, and inhibition of HDAC6 restores microtubule acetylation in BBIP1-depleted cells (loktev2008abbsomesubunit pages 1-2). This suggests that BBSome-bound BBIP1 may couple axonemal microtubule acetylation to ciliary membrane growth, although later genetic evidence in BBS patients suggests BBIP1 likely functions primarily through the BBSome (scheidecker2014exomesequencingof pages 4-6).
Mutations in BBIP1 cause Bardet-Biedl syndrome (BBS), designated as BBS18 (scheidecker2014exomesequencingof pages 1-3, scheidecker2014exomesequencingof pages 4-6). Scheidecker et al. (2014) reported the first BBS patient carrying a homozygous nonsense mutation in BBIP1 (c.173T>G, p.Leu58). This mutation results in complete loss of BBIP1 protein in patient fibroblasts, as detected by Western blot. Co-immunoprecipitation experiments demonstrated that the truncated BBIP1[Leu58] protein fails to associate efficiently with BBS4, confirming that BBSome assembly is severely compromised in the patient (scheidecker2014exomesequencingof pages 4-6).
More recently, Nawaz et al. (2023) identified additional families with biallelic BBIP1 variants presenting with clinical features of BBS, including retinal dystrophy, obesity, polydactyly, renal abnormalities, and developmental delay (scheidecker2014exomesequencingof pages 1-3). Zebrafish morpholino studies confirmed that BBIP1 loss causes characteristic BBS phenotypes including abnormal Kupffer's vesicle formation (affecting left-right asymmetry), delayed melanosome transport, and defective ciliogenesis (scheidecker2014exomesequencingof pages 4-6, loktev2008abbsomesubunit pages 4-5).
Despite extensive screening of over 300 BBS probands without mutations in known BBS genes, no additional coding sequence mutations in BBIP1 were initially identified (loktev2008abbsomesubunit pages 4-5), suggesting that BBIP1 mutations may be rare causes of BBS, possibly due to the small size of the gene making it a limited target for spontaneous mutations. However, recent 2023 reports indicate that BBIP1 mutations do contribute to the genetic spectrum of BBS (scheidecker2014exomesequencingof pages 1-3).
The pathogenic mechanism converges on defective BBSome assembly and trafficking. Most BBS alleles, including those in BBIP1, disrupt BBSome formation or function, leading to mislocalization of ciliary signaling receptors and consequent multi-organ pathology (tian2023organizationfunctionsand pages 1-2, scheidecker2014exomesequencingof pages 4-6, tian2023organizationfunctionsand pages 2-3).
Recent comprehensive reviews emphasize the BBSome's role as a master regulator of ciliary membrane proteome composition (tian2023organizationfunctionsand pages 1-2). Tian et al. (2023) provided an updated synthesis of BBSome organization, functions, and mechanisms in development and ciliopathies, highlighting progress in structural characterization and therapeutic development. Clinical genetics studies continue to expand the mutation spectrum, with biallelic BBIP1 variants identified in families with suspected BBS (scheidecker2014exomesequencingof pages 1-3).
Emerging research also addresses post-translational regulation of the BBSome. Chiuso et al. (2023) demonstrated that the E3 ubiquitin ligase PJA2 ubiquitylates BBSome subunits, including BBS1, upon GPCR-cAMP stimulation. Ubiquitylation of BBS1 at lysine 143 increases BBSome stability and promotes binding to ARL6/BBS3, affecting ciliary assembly and GPCR trafficking (chiuso2023ubiquitylationofbbsome pages 1-2). This finding reveals dynamic regulatory mechanisms beyond static assembly models and suggests that BBIP1 operates within a post-translationally regulated complex.
Therapeutic advances include the approval of setmelanotide, an MC4R agonist, for treatment of obesity in BBS patients (tian2023organizationfunctionsand pages 1-2). This treatment addresses downstream consequences of BBSome dysfunction affecting melanocortin pathway signaling in hypothalamic neurons, though it does not correct the underlying ciliary trafficking defect.
BBIP1 (BBSome-interacting protein 1) is an essential 10 kDa structural component of the octameric BBSome complex in human cells. Its primary function is to support BBSome assembly and stability, which is critical for the BBSome's role as a cargo adapter for ciliary membrane proteins. BBIP1 localizes to the primary cilium, basal body, and transition zone, where it functions as part of the BBSome to regulate trafficking of signaling receptors, particularly GPCRs, in and out of cilia.
BBIP1 participates in key ciliary signaling pathways including Hedgehog and GPCR signaling by ensuring proper ciliary receptor localization rather than acting as a direct signal transducer. It has a unique role among BBSome subunits in regulating cytoplasmic microtubule acetylation, although its primary pathogenic function appears to be through BBSome assembly. Loss of BBIP1 causes Bardet-Biedl syndrome (BBS18), characterized by retinal degeneration, obesity, polydactyly, renal anomalies, and developmental defects due to disrupted BBSome function and ciliary signaling abnormalities.
| Protein / aliases | Molecular function | Role in BBSome | Binding partners / interactions | Subcellular localization | Pathways / processes involved | Disease associations | Unique features / notable evidence | Key references |
|---|---|---|---|---|---|---|---|---|
| BBIP1; BBIP10; BBS18; BBSome-interacting protein 1 / of 10 kDa | Small structural/adaptor subunit of the BBSome; not an enzyme or transporter. Required for ciliogenesis and ciliary membrane protein trafficking; experimentally linked to cytoplasmic microtubule polymerization/acetylation regulation (loktev2008abbsomesubunit pages 1-2, tian2023organizationfunctionsand pages 1-2, singh2020structureandactivation pages 1-2) | Integral 8th subunit of the octameric BBSome together with BBS1/2/4/5/7/8/9; necessary for full BBSome integrity and function (scheidecker2014exomesequencingof pages 1-3, tian2023organizationfunctionsand pages 1-2, singh2020structureandactivation pages 1-2) | Strongly associates with the BBSome; co-purifies and co-sediments with BBS4 and other BBSome subunits; patient truncation Leu58* fails to associate efficiently with BBS4; BBSome localization depends on ARL6/BBS3 for ciliary entry; BBIP10 was also reported to physically interact with HDAC6 in the microtubule acetylation context (scheidecker2014exomesequencingof pages 1-3, jin2010theconservedbardetbiedl pages 1-2, loktev2008abbsomesubunit pages 3-4, scheidecker2014exomesequencingof pages 4-6, loktev2008abbsomesubunit pages 1-2) | Localizes precisely to the primary cilium and colocalizes with BBS4 there; BBSome is also enriched at the basal body / transition zone / ciliary membrane trafficking interface; unlike BBS4, BBIP1 was not detected at centriolar satellites in the original localization study (loktev2008abbsomesubunit pages 3-4, jin2009thebbsome pages 1-2, singh2020structureandactivation pages 1-2) | Ciliogenesis; ciliary membrane proteome organization; intraflagellar transport-linked trafficking; ciliary entry/exit of receptors; regulation of Hedgehog and GPCR signaling through receptor localization; possible coupling of axonemal membrane growth to microtubule acetylation (tian2023organizationfunctionsand pages 1-2, yang2020nearatomicstructuresof pages 1-2, wingfield2018traffickingofciliary pages 1-2, wei2012thebbsomecontrols pages 1-2) | Bardet-Biedl syndrome (BBS18). A homozygous stop mutation in human BBIP1 caused loss of protein and impaired BBSome assembly in a BBS patient; additional 2023 clinical reports identified biallelic BBIP1 variants in suspected BBS families (scheidecker2014exomesequencingof pages 1-3, scheidecker2014exomesequencingof pages 4-6) | Distinguished from other subunits by a reported microtubule acetylation/stability phenotype: BBIP10 depletion reduced cytoplasmic MT acetylation and ciliogenesis, and HDAC6 inhibition restored acetylation; however, later human genetic work suggested BBIP1 likely functions mainly through the BBSome in patients (loktev2008abbsomesubunit pages 1-2, loktev2008abbsomesubunit pages 4-5, scheidecker2014exomesequencingof pages 4-6) | Loktev et al. 2008; Scheidecker et al. 2014; Tian et al. 2023 (loktev2008abbsomesubunit pages 1-2, scheidecker2014exomesequencingof pages 1-3, tian2023organizationfunctionsand pages 1-2) |
| Primary function in human cells | Supports assembly/stability of the BBSome coat/adaptor complex that recognizes ciliary membrane cargo and links it to trafficking machinery rather than catalyzing a chemical reaction (jin2010theconservedbardetbiedl pages 1-2, singh2020structureandactivation pages 1-2, klink2020structureofthe pages 1-2) | BBIP1 is required for incorporation of subunits into a stable BBSome; loss of BBIP1 causes failure of BBS4 to incorporate into the BBSome and markedly reduces complex formation (loktev2008abbsomesubunit pages 4-5, scheidecker2014exomesequencingof pages 4-6) | Interacts functionally with the BBS-chaperonin assembly pathway (BBS6/BBS10/BBS12/CCT indirectly via BBSome biogenesis) and with core BBSome subunits during sequential assembly (zhang2012intrinsicproteinproteininteractionmediated pages 1-2, klink2020structureofthe pages 1-2) | Cytoplasmic assembly occurs before ciliary deployment; functional action is concentrated at the cilium/base of cilium after assembly (jin2009thebbsome pages 1-2, singh2020structureandactivation pages 1-2) | BBSome assembly, membrane coat formation, cargo recognition, receptor traffic across/near the transition zone (jin2010theconservedbardetbiedl pages 1-2, yang2020nearatomicstructuresof pages 1-2, singh2020structureandactivation pages 1-2) | BBS pathogenesis likely converges on defective BBSome assembly and/or trafficking (scheidecker2014exomesequencingof pages 4-6, tian2023organizationfunctionsand pages 1-2) | BBIP1 is small relative to other BBSome subunits but functionally indispensable; despite its size, pathogenic loss abolishes BBSome integrity (loktev2008abbsomesubunit pages 1-2, scheidecker2014exomesequencingof pages 4-6) | Zhang et al. 2012; Singh et al. 2020; Klink et al. 2020 (zhang2012intrinsicproteinproteininteractionmediated pages 1-2, singh2020structureandactivation pages 1-2, klink2020structureofthe pages 1-2) |
| Cargo-related role | Contributes to the BBSomeโs role as a cargo adapter for ciliary membrane proteins, especially signaling receptors such as GPCRs (wingfield2018traffickingofciliary pages 1-2, klink2020structureofthe pages 1-2) | As part of the octamer, helps enable recognition and trafficking of cargoes including SSTR3, Smoothened (SMO), and other ciliary receptors; cargo binding in current structural models is centered largely on the BBSome core cleft and BBS1-rich interfaces, but requires intact complex assembly that includes BBIP1 (jin2010theconservedbardetbiedl pages 1-2, yang2020nearatomicstructuresof pages 1-2, klink2020structureofthe pages 1-2) | Functionally linked with ARL6/BBS3-GTP, which recruits the BBSome to membranes and promotes active conformation; with IFT-A/IFT-B for ciliary transport; with receptor cargoes through the assembled BBSome (jin2010theconservedbardetbiedl pages 1-2, yang2020nearatomicstructuresof pages 1-2, wei2012thebbsomecontrols pages 1-2) | Ciliary membrane, transition zone, and along the axoneme during BBSome/IFT transit (nakayama2018ciliaryproteintrafficking pages 1-2, wingfield2018traffickingofciliary pages 1-2) | GPCR trafficking, removal of activated GPCRs from cilia, control of ciliary membrane composition (yang2020nearatomicstructuresof pages 1-2, wingfield2018traffickingofciliary pages 1-2) | Mis-trafficking of neuronal and developmental receptors contributes to obesity, retinal degeneration, and developmental anomalies in BBS (tian2023organizationfunctionsand pages 2-3, singh2020structureandactivation pages 1-2) | Recent consensus favors a major role in export/removal of selected membrane proteins from cilia, though historical work also implicated import/targeting to cilia (wingfield2018traffickingofciliary pages 1-2, singh2020structureandactivation pages 1-2) | Wingfield et al. 2018; Yang et al. 2020; Jin et al. 2010 (wingfield2018traffickingofciliary pages 1-2, yang2020nearatomicstructuresof pages 1-2, jin2010theconservedbardetbiedl pages 1-2) |
| Role in signaling | Indirect regulator of signaling by ensuring correct ciliary receptor composition rather than acting as a signaling enzyme/receptor itself (tian2023organizationfunctionsand pages 1-2, yang2020nearatomicstructuresof pages 1-2) | Necessary BBSome subunit for ciliary trafficking steps that position signaling molecules appropriately (tian2023organizationfunctionsand pages 1-2, seo2011anovelprotein pages 1-2) | Linked to Smoothened, GPR161, SSTR3, MCHR1, leptin receptor-associated pathways, and other ciliary GPCR systems through the BBSome (tian2023organizationfunctionsand pages 1-2, yang2020nearatomicstructuresof pages 1-2, tian2023organizationfunctionsand pages 2-3, seo2011anovelprotein pages 1-2) | Acts where signaling receptors are sorted: cilium, transition zone, ciliary membrane (singh2020structureandactivation pages 1-2, wingfield2018traffickingofciliary pages 1-2) | Hedgehog, GPCR, hypothalamic feeding-related receptor localization, broader cilia-dependent developmental signaling including Wnt/PDGF/TGF-ฮฒ contexts discussed for the BBSome literature (tian2023organizationfunctionsand pages 1-2, tian2023organizationfunctionsand pages 2-3, wingfield2018traffickingofciliary pages 1-2) | Aberrant receptor localization explains core BBS phenotypes such as polydactyly, retinal degeneration, obesity, and neurodevelopmental features (tian2023organizationfunctionsand pages 2-3, tian2023organizationfunctionsand pages 1-2) | BBIP1โs effect on signaling is best understood as a structural dependency of signaling-receptor trafficking on an intact BBSome (tian2023organizationfunctionsand pages 1-2, singh2020structureandactivation pages 1-2) | Tian et al. 2023; Seo et al. 2011; Yang et al. 2020 (tian2023organizationfunctionsand pages 1-2, seo2011anovelprotein pages 1-2, yang2020nearatomicstructuresof pages 1-2) |
| Structural / mechanistic context from recent work | No independent catalytic active site known; BBIP1 contributes to higher-order BBSome architecture and function as part of an evolutionarily conserved trafficking complex (tian2023organizationfunctionsand pages 1-2, klink2020structureofthe pages 1-2) | Included in modern cryo-EM and structural models of the native BBSome/BBSome core; these show the BBSome is an activated membrane-associated coat/adaptor whose conformation changes upon ARL6 binding (singh2020structureandactivation pages 1-2, yang2020nearatomicstructuresof pages 1-2, klink2020structureofthe pages 1-2) | Structural studies indicate cargo recognition involves a charged cleft and multiple subunits; BBIP1 is part of the intact machinery necessary for these interfaces to exist in vivo (klink2017arecombinantbbsome pages 1-2, klink2020structureofthe pages 1-2) | Structural action occurs in the assembled complex on/near ciliary membranes (yang2020nearatomicstructuresof pages 1-2, singh2020structureandactivation pages 1-2) | BBSome activation, membrane recruitment, coat polymerization, coupling to IFT transit (jin2010theconservedbardetbiedl pages 1-2, yang2020nearatomicstructuresof pages 1-2, chiuso2023ubiquitylationofbbsome pages 1-2) | Structural disruption of BBSome subunits causes ciliopathy; BBIP1 loss is one such disruptive lesion (scheidecker2014exomesequencingof pages 4-6, singh2020structureandactivation pages 1-2) | 2023 work further indicates BBSome regulation includes post-translational control such as ubiquitylation of BBS1, emphasizing that BBIP1 operates within a dynamically regulated complex rather than alone (chiuso2023ubiquitylationofbbsome pages 1-2) | Singh et al. 2020; Yang et al. 2020; Klink et al. 2020; Chiuso et al. 2023 (singh2020structureandactivation pages 1-2, yang2020nearatomicstructuresof pages 1-2, klink2020structureofthe pages 1-2, chiuso2023ubiquitylationofbbsome pages 1-2) |
Table: This table summarizes the verified identity, molecular function, localization, pathways, interactions, and disease relevance of human BBIP1/BBIP10/BBS18. It consolidates foundational and recent evidence to support functional annotation of BBIP1 as an essential BBSome subunit in ciliary trafficking and signaling.
References
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(loktev2008abbsomesubunit pages 1-2): Alexander V. Loktev, Qihong Zhang, John S. Beck, Charles C. Searby, Todd E. Scheetz, J. Fernando Bazan, Diane C. Slusarski, Val C. Sheffield, Peter K. Jackson, and Maxence V. Nachury. A bbsome subunit links ciliogenesis, microtubule stability, and acetylation. Developmental cell, 15 6:854-65, Dec 2008. URL: https://doi.org/10.1016/j.devcel.2008.11.001, doi:10.1016/j.devcel.2008.11.001. This article has 391 citations and is from a highest quality peer-reviewed journal.
(tian2023organizationfunctionsand pages 1-2): Xiaoyu Tian, Huijie Zhao, and Jun Zhou. Organization, functions, and mechanisms of the bbsome in development, ciliopathies, and beyond. eLife, Jul 2023. URL: https://doi.org/10.7554/elife.87623, doi:10.7554/elife.87623. This article has 84 citations and is from a domain leading peer-reviewed journal.
(jin2010theconservedbardetbiedl pages 1-2): Hua Jin, Susan Roehl White, Toshinobu Shida, Stefan Schulz, Mike Aguiar, Steven P. Gygi, J. Fernando Bazan, and Maxence V. Nachury. The conserved bardet-biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell, 141:1208-1219, Jun 2010. URL: https://doi.org/10.1016/j.cell.2010.05.015, doi:10.1016/j.cell.2010.05.015. This article has 714 citations and is from a highest quality peer-reviewed journal.
(loktev2008abbsomesubunit pages 4-5): Alexander V. Loktev, Qihong Zhang, John S. Beck, Charles C. Searby, Todd E. Scheetz, J. Fernando Bazan, Diane C. Slusarski, Val C. Sheffield, Peter K. Jackson, and Maxence V. Nachury. A bbsome subunit links ciliogenesis, microtubule stability, and acetylation. Developmental cell, 15 6:854-65, Dec 2008. URL: https://doi.org/10.1016/j.devcel.2008.11.001, doi:10.1016/j.devcel.2008.11.001. This article has 391 citations and is from a highest quality peer-reviewed journal.
(loktev2008abbsomesubunit pages 3-4): Alexander V. Loktev, Qihong Zhang, John S. Beck, Charles C. Searby, Todd E. Scheetz, J. Fernando Bazan, Diane C. Slusarski, Val C. Sheffield, Peter K. Jackson, and Maxence V. Nachury. A bbsome subunit links ciliogenesis, microtubule stability, and acetylation. Developmental cell, 15 6:854-65, Dec 2008. URL: https://doi.org/10.1016/j.devcel.2008.11.001, doi:10.1016/j.devcel.2008.11.001. This article has 391 citations and is from a highest quality peer-reviewed journal.
(zhang2012intrinsicproteinproteininteractionmediated pages 1-2): Qihong Zhang, Dahai Yu, Seongjin Seo, Edwin M. Stone, and Val C. Sheffield. Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the bbsome. Journal of Biological Chemistry, 287:20625-20635, Jun 2012. URL: https://doi.org/10.1074/jbc.m112.341487, doi:10.1074/jbc.m112.341487. This article has 204 citations and is from a domain leading peer-reviewed journal.
(yang2020nearatomicstructuresof pages 1-2): Shuang Yang, Kriti Bahl, Hui-Ting Chou, Jonathan Woodsmith, Ulrich Stelzl, Thomas Walz, and Maxence V Nachury. Near-atomic structures of the bbsome reveal the basis for bbsome activation and binding to gpcr cargoes. Jun 2020. URL: https://doi.org/10.7554/elife.55954, doi:10.7554/elife.55954. This article has 55 citations and is from a domain leading peer-reviewed journal.
(singh2020structureandactivation pages 1-2): Sandeep K Singh, Miao Gui, Fujiet Koh, Matthew CJ Yip, and Alan Brown. Structure and activation mechanism of the bbsome membrane protein trafficking complex. Jan 2020. URL: https://doi.org/10.7554/elife.53322, doi:10.7554/elife.53322. This article has 105 citations and is from a domain leading peer-reviewed journal.
(wingfield2018traffickingofciliary pages 1-2): Jenna L. Wingfield, Karl-Ferdinand Lechtreck, and Esben Lorentzen. Trafficking of ciliary membrane proteins by the intraflagellar transport/bbsome machinery. Essays in biochemistry, 62 6:753-763, Oct 2018. URL: https://doi.org/10.1042/ebc20180030, doi:10.1042/ebc20180030. This article has 183 citations and is from a peer-reviewed journal.
(klink2020structureofthe pages 1-2): Bjรถrn Udo Klink, Christos Gatsogiannis, Oliver Hofnagel, Alfred Wittinghofer, and Stefan Raunser. Structure of the human bbsome core complex. eLife, Jan 2020. URL: https://doi.org/10.7554/elife.53910, doi:10.7554/elife.53910. This article has 97 citations and is from a domain leading peer-reviewed journal.
(jin2009thebbsome pages 1-2): Hua Jin and Maxence V. Nachury. The bbsome. Current Biology, 19:R472-R473, Jun 2009. URL: https://doi.org/10.1016/j.cub.2009.04.015, doi:10.1016/j.cub.2009.04.015. This article has 102 citations and is from a highest quality peer-reviewed journal.
(nakayama2018ciliaryproteintrafficking pages 1-2): Kazuhisa Nakayama and Yohei Katoh. Ciliary protein trafficking mediated by ift and bbsome complexes with the aid of kinesin-2 and dynein-2 motors. Journal of biochemistry, 163 3:155-164, Mar 2018. URL: https://doi.org/10.1093/jb/mvx087, doi:10.1093/jb/mvx087. This article has 160 citations and is from a peer-reviewed journal.
(wei2012thebbsomecontrols pages 1-2): Qing Wei, Yuxia Zhang, Yujie Li, Qing Zhang, Kun Ling, and Jinghua Hu. The bbsome controls ift assembly and turnaround in cilia. Aug 2012. URL: https://doi.org/10.1038/ncb2560, doi:10.1038/ncb2560. This article has 271 citations and is from a highest quality peer-reviewed journal.
(seo2011anovelprotein pages 1-2): Seongjin Seo, Qihong Zhang, Kevin Bugge, David K. Breslow, Charles C. Searby, Maxence V. Nachury, and Val C. Sheffield. A novel protein lztfl1 regulates ciliary trafficking of the bbsome and smoothened. PLoS Genetics, 7:e1002358, Nov 2011. URL: https://doi.org/10.1371/journal.pgen.1002358, doi:10.1371/journal.pgen.1002358. This article has 264 citations and is from a domain leading peer-reviewed journal.
(tian2023organizationfunctionsand pages 2-3): Xiaoyu Tian, Huijie Zhao, and Jun Zhou. Organization, functions, and mechanisms of the bbsome in development, ciliopathies, and beyond. eLife, Jul 2023. URL: https://doi.org/10.7554/elife.87623, doi:10.7554/elife.87623. This article has 84 citations and is from a domain leading peer-reviewed journal.
(scheidecker2014exomesequencingof pages 4-6): Sophie Scheidecker, Christelle Etard, Nathan W Pierce, Vรฉronique Geoffroy, Elise Schaefer, Jean Muller, Kirsley Chennen, Elisabeth Flori, Valรฉrie Pelletier, Olivier Poch, Vincent Marion, Corinne Stoetzel, Uwe Strรคhle, Maxence V Nachury, and Hรฉlรจne Dollfus. Exome sequencing of bardetโbiedl syndrome patient identifies a null mutation in the bbsome subunit bbip1 (bbs18). Journal of Medical Genetics, 51:132-136, Sep 2014. URL: https://doi.org/10.1136/jmedgenet-2013-101785, doi:10.1136/jmedgenet-2013-101785. This article has 190 citations and is from a domain leading peer-reviewed journal.
(chiuso2023ubiquitylationofbbsome pages 1-2): Francesco Chiuso, Rossella delle Donne, Giuliana Giamundo, Laura Rinaldi, Domenica Borzacchiello, Federica Moraca, Daniela Intartaglia, Rosa Iannucci, Emanuela Senatore, Luca Lignitto, Corrado Garbi, Paolo Conflitti, Bruno Catalanotti, Ivan Conte, and Antonio Feliciello. Ubiquitylation of bbsome is required for ciliary assembly and signaling. EMBO Reports, Feb 2023. URL: https://doi.org/10.15252/embr.202255571, doi:10.15252/embr.202255571. This article has 19 citations and is from a highest quality peer-reviewed journal.
(klink2017arecombinantbbsome pages 1-2): Bjรถrn Udo Klink, Eldar Zent, Puneet Juneja, Anne Kuhlee, Stefan Raunser, and Alfred Wittinghofer. A recombinant bbsome core complex and how it interacts with ciliary cargo. eLife, Nov 2017. URL: https://doi.org/10.7554/elife.27434, doi:10.7554/elife.27434. This article has 88 citations and is from a domain leading peer-reviewed journal.
PMID:19081074 (Loktev et al., Dev Cell 2008; abstract-only in cache, full_text_available: false;
corresponds to UniProt "Ref.4" Loktev et al. supplying FUNCTION/SUBUNIT/SUBCELLULAR LOCATION/HDAC6 interaction):
- Discovered BBIP10 as the eighth BBSome subunit. "We have now discovered a BBSome subunit that
we named BBIP10. Similar to other BBSome subunits, BBIP10 localizes to the primary cilium,
BBIP10 is present exclusively in ciliated organisms"
PMID:19081074.
- Depletion produces canonical BBS phenotypes in zebrafish
PMID:19081074.
- A unique (non-BBSome-shared) function: required for cytoplasmic microtubule polymerization and
acetylation PMID:19081074.
- Mechanism links to the tubulin deacetylase HDAC6: "inhibition of the tubulin deacetylase HDAC6
restores microtubule acetylation in BBIP10-depleted cells, and BBIP10 physically interacts with HDAC6"
PMID:19081074. HDAC6 = UniProt Q9UBN7 (the WITH/FROM in the GOA IPI row).
- Model: "BBSome-bound BBIP10 may therefore function to couple acetylation of axonemal microtubules
and ciliary membrane growth" PMID:19081074.
UniProt FUNCTION (from Ref.4): "Required for primary cilia assembly and BBSome stability. Regulates
cytoplasmic microtubule stability and acetylation." SUBUNIT: "Part of BBSome complex, that contains
BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. Interacts with HDAC6." SUBCELLULAR LOCATION:
"Cell projection, cilium. Cytoplasm. Note=Localizes inside the primary cilium but not at centriolar satellites."
PMID:22500027 (Zhang et al., JBC 2012; full text available):
- BBIP10 is "an integral BBSome protein that binds to the complex through BBS4"
PMID:22500027.
- PCM1 can interact with BBIP10 only when BBS4 is present PMID:22500027.
- Establishes ordered BBSome assembly (core BBS7-BBS2-BBS9; then BBS1, BBS5, BBS8, BBS4).
- The GOA IPI row from this paper uses WITH/FROM UniProtKB:Q96RK4 (= BBS4), consistent with the
BBIP10โBBS4 binding shown here. Supports a BBSome part_of / structural-binding annotation.
PMID:29039417 (Woodsmith et al., Nat Methods 2017; abstract-only):
- Yeast two-hybrid "off-switch" perturbation profiling across "eight subunits of the BBSome"; defined
1,000 interaction-disrupting mutations PMID:29039417. BBIP1 included as one of the eight subunits.
- GOA IPI row also uses WITH/FROM Q96RK4 (BBS4). Supports BBIP1 participating in BBSome via PPIs;
generic "protein binding" (GO:0005515) is uninformative.
PMID:24026985 (Scheidecker et al., J Med Genet 2014; not cached, cited in UniProt Ref.5):
- A null mutation in BBIP1 causes Bardet-Biedl syndrome 18 (BBS18) [MIM:615995]. Confirms BBIP1 as a
bona fide BBSome subunit whose loss causes BBS (severe retinopathy, obesity, polydactyly, renal,
intellectual disability).
id: A8MTZ0
gene_symbol: BBIP1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
BBIP1 (also known as BBIP10 and BBS18) is the small (92 aa, ~10.5 kDa) eighth
core subunit of the BBSome, an octameric, coat-like adaptor complex (BBS1, BBS2,
BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10) that traffics signaling membrane
receptors, including ciliary GPCRs, into and out of the primary cilium in
conjunction with intraflagellar transport and the small GTPase ARL6/BBS3. BBIP1
is an integral, stably incorporated subunit that joins the complex through BBS4
and is required for BBSome integrity/stability and for primary cilium assembly.
It is found inside the primary cilium and in the cytoplasm but not at centriolar
satellites. Beyond its structural role in the BBSome, BBIP1 has a distinct
activity not shared by other BBSome subunits; it is required for cytoplasmic
microtubule polymerization and acetylation, acting in part through physical
interaction with the tubulin deacetylase HDAC6. BBIP1 is restricted to ciliated
organisms, and loss-of-function mutations cause the ciliopathy Bardet-Biedl
syndrome type 18.
alternative_products:
- name: '1'
id: A8MTZ0-1
- name: '2'
id: A8MTZ0-2
sequence_note: VSP_045981
- name: '3'
id: A8MTZ0-3
sequence_note: VSP_046434
- name: '4'
id: A8MTZ0-4
sequence_note: VSP_046433
existing_annotations:
- term:
id: GO:0034464
label: BBSome
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: BBIP1/BBIP10 is a bona fide, experimentally validated core subunit of
the BBSome. The phylogenetic (IBA) call agrees with direct experimental evidence.
action: ACCEPT
reason: BBIP10 was discovered and characterized as the eighth BBSome subunit
and is an integral component that binds the complex through BBS4. This is a
core cellular-component annotation for the gene.
- term:
id: GO:0097500
label: receptor localization to non-motile cilium
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: The BBSome's central, defining function is trafficking signaling
receptors (e.g. ciliary GPCRs) into and out of the primary (non-motile)
cilium. As an integral subunit required for BBSome integrity, BBIP1 is
appropriately annotated to this process.
action: ACCEPT
reason: Term definition (a receptor is transported to, or maintained in, a
location within a non-motile cilium) matches the established BBSome cargo-
trafficking role; this is a core biological process for the gene.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: UniProt records BBIP1 in the cytoplasm, consistent with its cytoplasmic
microtubule role and with BBSome subunits cycling through the cytoplasm before
ciliary entry. This IEA call is corroborated by the experimental IDA below.
action: KEEP_AS_NON_CORE
reason: Correct but generic localization; the informative CC annotations are
BBSome, cilium, and ciliary membrane. Retain as supporting context.
- term:
id: GO:0005929
label: cilium
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: BBIP1 localizes inside the primary cilium, like other BBSome subunits.
The UniProt subcellular-location-derived IEA is consistent with experimental
data.
action: ACCEPT
reason: Ciliary localization is well supported experimentally and is central to
BBIP1/BBSome function.
- term:
id: GO:0034464
label: BBSome
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: part_of
review:
summary: InterPro2GO (IPR028233, BBIP10 family) maps the BBSome membership. This
is redundant with, and corroborated by, the experimental BBSome annotations.
action: ACCEPT
reason: Family-level electronic inference correctly assigns BBSome membership,
consistent with direct evidence.
- term:
id: GO:0060271
label: cilium assembly
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: BBIP1 is required for primary cilium assembly; the InterPro2GO electronic
inference agrees with the experimental IMP from the same depletion study.
action: ACCEPT
reason: Cilium assembly is a core, experimentally supported process for BBIP1;
the IEA is corroborated.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19081074
qualifier: enables
review:
summary: This IPI (WITH BBS4/Q96RK4) records a real, meaningful interaction
(BBIP10 binds the BBSome through BBS4), but the term "protein binding" is
uninformative and discouraged. The biological meaning is captured by the
BBSome part_of annotations and, separately, by the HDAC6 interaction.
action: MARK_AS_OVER_ANNOTATED
reason: GO:0005515 conveys no specific function; the underlying BBS4 interaction
is already represented by BBSome membership. Per curation guidance, avoid
bare protein binding.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22500027
qualifier: enables
review:
summary: Same uninformative term, supported by the BBSome assembly study showing
BBIP10 binds the complex via BBS4. Better represented as BBSome membership.
action: MARK_AS_OVER_ANNOTATED
reason: Protein binding is not an informative molecular function; the specific
interaction is captured by the BBSome part_of annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29039417
qualifier: enables
review:
summary: High-throughput Y2H perturbation profiling across the eight BBSome
subunits (WITH BBS4/Q96RK4). Confirms BBIP1 PPIs within the BBSome but yields
only the generic protein-binding term.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative MF term; the meaningful content (BBSome subunit interactions)
is captured by BBSome membership annotations.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5617815
qualifier: located_in
review:
summary: Reactome places the BBSome (and thus BBIP1) in the cytosol during
pathway steps prior to ciliary entry. Consistent with cytoplasmic localization
but less specific than the BBSome/ciliary CCs.
action: KEEP_AS_NON_CORE
reason: Plausible and curator-asserted (TAS), but generic; the informative
localizations are BBSome, cilium, ciliary membrane.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5624125
qualifier: located_in
review:
summary: Duplicate cytosol localization from the Reactome Formation of the
BBSome reaction.
action: KEEP_AS_NON_CORE
reason: Correct but generic localization; retain as supporting, non-core.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5624126
qualifier: located_in
review:
summary: Duplicate cytosol localization from a Reactome BBSome cargo-binding
reaction.
action: KEEP_AS_NON_CORE
reason: Correct but generic localization; retain as supporting, non-core.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5624127
qualifier: located_in
review:
summary: Duplicate cytosol localization from a Reactome BBSome cargo-targeting
reaction.
action: KEEP_AS_NON_CORE
reason: Correct but generic localization; retain as supporting, non-core.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5624129
qualifier: located_in
review:
summary: Duplicate cytosol localization from the Reactome LZTFL1-BBSome reaction.
action: KEEP_AS_NON_CORE
reason: Correct but generic localization; retain as supporting, non-core.
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: HPA immunofluorescence places BBIP1 in the cytosol. Consistent with
cytoplasmic localization and the cytoplasmic microtubule role, though generic.
action: KEEP_AS_NON_CORE
reason: Experimentally observed but non-specific localization; informative CCs
are BBSome, cilium, ciliary membrane.
- term:
id: GO:0036064
label: ciliary basal body
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: HPA immunofluorescence localizes BBIP1 to the ciliary basal body. The
BBSome traffics through the basal body en route to the cilium, so this is
plausible. Note UniProt states BBIP1 localizes inside the cilium but NOT at
centriolar satellites; basal body is distinct from satellites.
action: ACCEPT
reason: Experimental (IDA) localization consistent with the BBSome trafficking
route through the basal body; defer to the experimental call.
supported_by:
- reference_id: file:human/BBIP1/BBIP1-deep-research-falcon.md
supporting_text: >-
is present along the ciliary axoneme but not at centriolar satellites
- term:
id: GO:0034464
label: BBSome
evidence_type: IPI
original_reference_id: PMID:19081074
qualifier: part_of
review:
summary: Direct experimental evidence (mass-spec identification of BBIP10 within
the purified BBSome; ComplexPortal CPX-1908) establishes BBIP1 as a BBSome
subunit. This is the strongest CC annotation.
action: ACCEPT
reason: Core, experimentally validated cellular-component annotation; defining
identity of the gene product.
- term:
id: GO:0060170
label: ciliary membrane
evidence_type: IDA
original_reference_id: PMID:19081074
qualifier: located_in
review:
summary: The BBSome acts as a membrane coat at the ciliary membrane and BBIP10
localizes within the cilium. ComplexPortal IDA annotation to ciliary membrane
reflects where the complex functions.
action: ACCEPT
reason: Consistent with the BBSome coat function at the ciliary membrane and with
BBIP1's ciliary localization; experimentally supported.
- term:
id: GO:0060271
label: cilium assembly
evidence_type: NAS
original_reference_id: PMID:19081074
qualifier: involved_in
review:
summary: Non-traceable author statement of the cilium-assembly role from the
discovery paper. The same process is independently supported by the IMP
annotation below.
action: ACCEPT
reason: Correct process; redundant with stronger IMP evidence from the same study.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:19081074
qualifier: located_in
review:
summary: Direct experimental observation of cytoplasmic BBIP1, consistent with
UniProt subcellular location and with its cytoplasmic microtubule function.
action: KEEP_AS_NON_CORE
reason: Experimentally observed but generic localization; informative CCs are
BBSome, cilium, ciliary membrane.
- term:
id: GO:0034464
label: BBSome
evidence_type: IDA
original_reference_id: PMID:19081074
qualifier: part_of
review:
summary: Direct experimental evidence (UniProt-curated IDA) that BBIP10 is part
of the BBSome.
action: ACCEPT
reason: Core, experimentally validated BBSome membership; defining function.
- term:
id: GO:0060271
label: cilium assembly
evidence_type: IMP
original_reference_id: PMID:19081074
qualifier: involved_in
review:
summary: BBIP10 depletion impairs ciliogenesis (characteristic BBS phenotypes in
zebrafish; ciliary defects in cells). Strong mutant-phenotype evidence for a
role in cilium assembly.
action: ACCEPT
reason: Experimental IMP for a core biological process; the gene is required for
primary cilium assembly.
- term:
id: GO:0005198
label: structural molecule activity
evidence_type: IDA
original_reference_id: PMID:19081074
qualifier: enables
review:
summary: >-
Proposed new molecular-function annotation. BBIP1 is an integral structural
subunit that contributes to BBSome integrity/stability; this captures its
subunit-level structural role, which is currently only implied by the generic
protein-binding IPIs. The falcon deep research summarizes the subunit-specific
assembly requirement, noting that BBIP1 depletion prevents BBSome assembly and
causes BBS4 to fail to copurify with the other subunits.
action: NEW
reason: Captures BBIP1's structural contribution to the BBSome (required for
BBSome stability), a more informative molecular function than protein binding.
This is genuinely subunit-specific (a depletion phenotype of BBIP1 itself),
not merely inferred from holo-complex function.
proposed_replacement_terms:
- id: GO:0005198
label: structural molecule activity
supported_by:
- reference_id: file:human/BBIP1/BBIP1-deep-research-falcon.md
supporting_text: >-
Depletion of BBIP1 by siRNA prevents the assembly of the BBSome, as
demonstrated by metabolic labeling experiments showing that BBS4 fails to
copurify with other BBSome subunits in BBIP1-depleted cells
- term:
id: GO:0046785
label: microtubule polymerization
evidence_type: IMP
original_reference_id: PMID:19081074
qualifier: involved_in
review:
summary: Proposed new biological-process annotation capturing BBIP1's distinct,
non-BBSome-shared role in cytoplasmic microtubule polymerization and
acetylation (rescued by HDAC6 inhibition; BBIP1 binds HDAC6). Not currently
represented in GOA. The falcon deep research independently emphasizes that this
microtubule-acetylation phenotype is specific to the BBIP1 subunit and is not
seen on depletion of other BBSome subunits.
action: NEW
reason: BBIP10 depletion abolishes cytoplasmic microtubule polymerization and
acetylation, a function explicitly distinguished from its BBSome role.
proposed_replacement_terms:
- id: GO:0046785
label: microtubule polymerization
supported_by:
- reference_id: file:human/BBIP1/BBIP1-deep-research-falcon.md
supporting_text: >-
Depletion of BBIP1 results in marked reduction of cytoplasmic microtubule
acetylation and dramatically decreased ciliogenesis, phenotypes not observed
with depletion of other BBSome subunits
- term:
id: GO:0060090
label: molecular adaptor activity
evidence_type: IPI
original_reference_id: PMID:19081074
qualifier: enables
review:
summary: Proposed new molecular-function annotation. BBIP1 physically interacts
with the tubulin deacetylase HDAC6, and this interaction underlies its
promotion of microtubule acetylation; an adaptor activity is a more
informative MF than the generic protein-binding IPI from the same paper.
action: NEW
reason: BBIP1 binds HDAC6 (with BBS4/Q96RK4) and couples the BBSome to tubulin
acetylation; molecular adaptor activity captures this bridging role.
proposed_replacement_terms:
- id: GO:0060090
label: molecular adaptor activity
supported_by:
- reference_id: file:human/BBIP1/BBIP1-deep-research-falcon.md
supporting_text: >-
BBIP1 physically interacts with HDAC6, a tubulin deacetylase, and inhibition
of HDAC6 restores microtubule acetylation in BBIP1-depleted cells
core_functions:
- description: BBIP1/BBIP10 is an integral structural subunit of the BBSome that joins
the complex through BBS4 and is required for BBSome integrity/stability; the
assembled BBSome acts as a coat-like adaptor that, with ARL6/BBS3 and IFT,
traffics signaling receptors into and out of the primary cilium.
molecular_function:
id: GO:0005198
label: structural molecule activity
directly_involved_in:
- id: GO:0097500
label: receptor localization to non-motile cilium
- id: GO:0060271
label: cilium assembly
supported_by:
- reference_id: PMID:19081074
supporting_text: We have now discovered a BBSome subunit that we named BBIP10.
Similar to other BBSome subunits, BBIP10 localizes to the primary cilium.
- reference_id: PMID:22500027
supporting_text: BBIP10, an integral BBSome protein that binds to the complex
through BBS4.
- description: Independently of the rest of the BBSome, BBIP1 is required for
cytoplasmic microtubule polymerization and acetylation, acting in part through
physical interaction with the tubulin deacetylase HDAC6.
molecular_function:
id: GO:0060090
label: molecular adaptor activity
directly_involved_in:
- id: GO:0046785
label: microtubule polymerization
supported_by:
- reference_id: PMID:19081074
supporting_text: BBIP10 is required for cytoplasmic microtubule polymerization and
acetylation, two functions not shared with any other BBSome subunits.
- reference_id: PMID:19081074
supporting_text: inhibition of the tubulin deacetylase HDAC6 restores microtubule
acetylation in BBIP10-depleted cells, and BBIP10 physically interacts with HDAC6.
proposed_new_terms: []
suggested_questions:
- question: Is the microtubule-stabilizing/acetylation function of BBIP1 mediated by
BBSome-bound BBIP1 or by a free pool of BBIP1, and does it depend on direct HDAC6
inhibition versus an indirect mechanism?
experts:
- Maxence V. Nachury
- question: Does BBIP1 contribute specific structural contacts within the cryo-EM
BBSome architecture that are required for cargo (GPCR) capture or membrane
coating, beyond simply stabilizing the complex?
suggested_experiments:
- description: Separation-of-function mutagenesis of BBIP1 to uncouple BBSome
incorporation (BBS4 binding) from HDAC6 binding/microtubule acetylation, assayed
by ciliary GPCR trafficking versus cytoplasmic microtubule acetylation in
BBIP1-null cells.
hypothesis: BBIP1's BBSome-structural role and its microtubule/HDAC6-related role
are genetically separable functions of the same small protein.
- description: Map the BBIP1-HDAC6 interaction interface and test whether BBIP1
directly inhibits HDAC6 tubulin-deacetylase activity in vitro.
hypothesis: BBIP1 promotes microtubule acetylation by directly antagonizing HDAC6
rather than by an indirect cellular mechanism.
references:
- id: file:human/BBIP1/BBIP1-deep-research-falcon.md
title: Falcon deep research report for BBIP1
findings: []
reference_review:
relevance: HIGH
correctness: UNVERIFIED
review_notes: >-
LLM-synthesized (Edison Scientific) deep-research report. Correctly identifies
BBIP1/BBIP10/BBS18 as the small eighth BBSome subunit and accurately separates
the two subunit-specific lines of evidence from Loktev et al. 2008 (PMID:19081074):
(i) that BBIP1/BBIP10 depletion specifically prevents BBSome assembly with BBS4
failing to copurify, and (ii) that BBIP1 depletion reduces cytoplasmic microtubule
acetylation/polymerization "not observed with depletion of other BBSome subunits"
and that BBIP1 physically interacts with HDAC6. It also adds the Scheidecker et al.
2014 BBS18 patient evidence that the p.Leu58* truncation fails to associate with
BBS4. CAUTION: much of the report (Hedgehog/GPCR/IFT/ARL6 signaling, cargo
recognition, cryo-EM coat conformation) describes whole-BBSome (holo-complex)
functions and is only inferentially attributed to the BBIP1 subunit; the report
itself notes cargo binding is "centered largely on the BBSome core cleft and
BBS1-rich interfaces." Subunit-specific BBIP1 claims used here are restricted to
BBSome assembly/integrity and the microtubule-acetylation/HDAC6 role; citations
not independently re-verified against full text (hence UNVERIFIED), though they are
consistent with the cached PMID:19081074 and PMID:22500027 records.
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: PMID:19081074
title: A BBSome subunit links ciliogenesis, microtubule stability, and acetylation.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Discovery and primary characterization of BBIP10 as the eighth
BBSome subunit; establishes ciliary/cytoplasmic localization, requirement for
ciliogenesis (zebrafish/cell depletion), and the unique cytoplasmic microtubule
polymerization/acetylation role via HDAC6. Abstract-only in cache; this is
UniProt Ref.4 (Loktev et al., Dev Cell 2008) underpinning the UniProt FUNCTION,
SUBUNIT and SUBCELLULAR LOCATION statements.
- id: PMID:22500027
title: Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential
assembly of stable bardet-biedl syndrome protein complex, the BBSome.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Full text available; explicitly states BBIP10 is an integral
BBSome protein that binds to the complex through BBS4, and that PCM1 interacts
with BBIP10 only when BBS4 is present. Supports BBSome membership and the BBS4
(Q96RK4) interaction underlying the IPI annotation.
- id: PMID:29039417
title: Protein interaction perturbation profiling at amino-acid resolution.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Abstract-only; high-throughput Y2H perturbation profiling across
the eight BBSome subunits (BBIP1 included), defining over 1000 interaction-
disrupting mutations. Supports BBSome PPIs but only yields generic protein
binding.
- id: Reactome:R-HSA-5617815
title: BBSome binds RAB3IP
findings: []
- id: Reactome:R-HSA-5624125
title: Formation of the BBSome
findings: []
- id: Reactome:R-HSA-5624126
title: ARL6:GTP and the BBSome bind ciliary cargo
findings: []
- id: Reactome:R-HSA-5624127
title: ARL6:GTP and the BBSome target cargo to the primary cilium
findings: []
- id: Reactome:R-HSA-5624129
title: LZTFL1 binds the BBSome and prevents its traffic to the cilium
findings: []