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CCDC28B

Coiled-coil domain-containing protein 28B · UniProt Q9BUN5

Length
200 aa
Mass
22.0 kDa
Annotated
2026-06-09
17 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC28B is a pericentriolar coiled-coil protein that functions in ciliogenesis and acts as a second-site modifier of Bardet-Biedl syndrome, where heterozygous loss-of-function alleles epistatically enhance BBS phenotypes in vivo (PMID:16327777). It physically associates and colocalizes with BBS proteins at the pericentriole, and its depletion in cultured cells and zebrafish produces defective ciliogenesis with hallmark ciliopathy readouts including hydrocephalus, left-right axis defects, and renal impairment (PMID:16327777, PMID:23015189). CCDC28B controls cilia length through several interactions: it binds SIN1 and positively regulates mTORC2 assembly and activity without affecting mTORC1, with SIN1 itself contributing to cilia length in a manner independent of mTOR signaling (PMID:23727834); and it binds the kinesin 1 motor components KLC1 and KIF5B, which restrict CCDC28B nuclear accumulation, such that a CCDC28B mutant lacking its nuclear localization motif fails to rescue the zebrafish ciliopathy phenotype (PMID:29445114). Beyond cilia, in T cells CCDC28B promotes immune synapse assembly by recruiting the actin regulator WASH to retromer at early endosomes via FAM21, driving actin polymerization and polarized TCR recycling; a CVID-associated R25W variant fails to bind FAM21 and impairs this recycling (PMID:34294890). CRISPR knockout mice show only mild tissue-specific cilia defects without retinal degeneration or obesity but display social interaction defects and stereotypical behaviors (PMID:35653384).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2005 High

    Established CCDC28B as a pericentriolar BBS-interacting protein and a genetic modifier of Bardet-Biedl syndrome, answering whether a non-core locus could epistatically shape ciliopathy severity.

    Evidence Co-IP/colocalization with BBS proteins, cryptic splice-site analysis of the C430T mutation, and zebrafish morpholino epistasis with BBS morphants

    PMID:16327777

    Open questions at the time
    • Molecular mechanism by which CCDC28B modifies BBS protein function not defined
    • Direct binding partner among BBS proteins not pinpointed
  2. 2012 High

    Demonstrated that CCDC28B is required for ciliogenesis itself rather than acting solely as a modifier, linking its loss to organ-level ciliopathy phenotypes.

    Evidence siRNA/morpholino knockdown in cells and zebrafish with ciliogenesis assays and ciliopathy phenotyping; in silico phylogenetics restricting orthologs to ciliated metazoa

    PMID:23015189

    Open questions at the time
    • Molecular step in cilium assembly controlled by CCDC28B unresolved
    • Whether the ciliogenesis defect is cell-autonomous not addressed
  3. 2013 High

    Identified a biochemical pathway for cilia-length control by showing CCDC28B binds SIN1 and positively regulates mTORC2, while uncoupling SIN1's cilia role from mTOR signaling.

    Evidence Reciprocal Co-IP, mTORC2 activity assays, and zebrafish morpholino epistasis; Rictor depletion fails to shorten cilia

    PMID:23727834

    Open questions at the time
    • The mTOR-independent mechanism by which SIN1 sets cilia length is undefined
    • How CCDC28B promotes mTORC2 assembly structurally is unknown
  4. 2018 High

    Connected CCDC28B subcellular trafficking to cilia length by showing kinesin 1 binding restricts its nuclear accumulation, with the nuclear localization motif required for function.

    Evidence Co-IP with KLC1/KIF5B, NLS mutagenesis, subcellular localization assays, and in vivo rescue/epistasis in zebrafish

    PMID:29445114

    Open questions at the time
    • What CCDC28B does in the nucleus versus cytoplasm at the molecular level is unclear
    • How nuclear/cytoplasmic partitioning is mechanistically coupled to cilium length not resolved
  5. 2021 High

    Revealed a non-ciliary function in T cells, showing CCDC28B drives immune synapse assembly by recruiting WASH to retromer via FAM21 to enable polarized TCR recycling.

    Evidence Co-IP with FAM21, R25W variant functional assay, TCR recycling and IS imaging, and rescue by wild-type overexpression in CVID patient T cells

    PMID:34294890

    Open questions at the time
    • Whether the endosomal/retromer role generalizes to ciliated cells is not established
    • Structural basis of the CCDC28B-FAM21 interaction disrupted by R25W not defined
  6. 2022 Medium

    Tested organismal requirement in mammals, finding CCDC28B loss causes only mild cilia defects but behavioral abnormalities, indicating context-dependent and possibly redundant cilia roles.

    Evidence CRISPR/Cas9 knockout mouse with histological cilia analysis and behavioral assays

    PMID:35653384

    Open questions at the time
    • Mechanism linking CCDC28B to social/stereotypic behavior unknown
    • Reason for absence of retinal degeneration and obesity despite ciliary role not explained
    • Single-lab characterization with limited mechanistic depth

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCDC28B integrates its pericentriolar/ciliary functions with its endosomal immune-synapse role within a single biochemical framework remains unresolved.
  • No unified model linking BBS modification, mTORC2/SIN1, kinesin trafficking, and WASH/retromer recruitment
  • No structural characterization of the coiled-coil interaction surfaces

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 1 GO:0005768 endosome 1 GO:0005815 microtubule organizing center 1 GO:0005929 cilium 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1 R-HSA-168256 Immune System 1
Partners
FAM21KIF5BKLC1SIN1WASH
Complex memberships
mTORC2retromer

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 MGC1203 (CCDC28B) encodes a pericentriolar protein that interacts and colocalizes with BBS proteins. A C430T mutation enhances use of a cryptic splice acceptor site, introducing a premature termination codon and reducing steady-state MGC1203 mRNA levels. Modest suppression of mgc1203 in zebrafish exerts an epistatic effect on the developmental phenotype of BBS morphants. Co-immunoprecipitation/colocalization, splice site analysis, zebrafish morpholino epistasis Nature High 16327777
2012 CCDC28B affects ciliogenesis both in cultured cells and in vivo in zebrafish. Depletion of Ccdc28b in zebrafish results in defective ciliogenesis and causes ciliopathy phenotypes including hydrocephalus, left-right axis determination defects, and renal function impairment. In silico analysis shows CCDC28B homologous sequences are restricted to ciliated metazoa. siRNA/morpholino knockdown in cells and zebrafish, ciliogenesis assays, in silico phylogenetic analysis Human genetics High 23015189
2013 CCDC28B interacts with SIN1, a component of mTOR complex 2 (mTORC2), and acts as a positive regulator of mTORC2, participating in its assembly/stability and modulating its activity without affecting mTORC1 function. CCDC28B regulates cilia length in vivo at least in part through its interaction with SIN1. Importantly, depletion of Rictor (another core mTORC2 component) does not result in shortened cilia, indicating SIN1's role in cilia length is likely independent of mTOR signaling. Co-immunoprecipitation, mTORC2 activity assays, zebrafish morpholino knockdown, genetic interaction studies Human molecular genetics High 23727834
2018 CCDC28B interacts with kinesin light chain 1 (KLC1) and kinesin heavy chain KIF5B (kinesin 1). Depletion of kinesin 1 components results in abnormally elongated cilia. Kinesin 1 regulates ciliogenesis through CCDC28B via genetic interaction. Kinesin 1 regulates the subcellular distribution of CCDC28B by inhibiting its nuclear accumulation. A CCDC28B mutant lacking a nuclear localization motif fails to rescue the ciliopathy phenotype in zebrafish morphant embryos. Co-immunoprecipitation, morpholino knockdown in zebrafish, subcellular localization assays, nuclear localization motif mutagenesis, genetic interaction studies Scientific reports High 29445114
2021 CCDC28B participates in immune synapse (IS) assembly in T cells by regulating polarized T-cell antigen receptor (TCR) recycling. This involves CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. A CVID-associated variant CCDC28BR25W fails to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C>T allele display IS defects correctable by overexpression of wild-type CCDC28B. Co-immunoprecipitation, variant functional assay (R25W mutant), TCR recycling assays, IS assembly imaging, rescue by wild-type overexpression Cell death and differentiation High 34294890
2022 Ccdc28b mutant mice (generated by CRISPR/Cas9) show mild defects in cilia density and cilia length in some tissues but do not develop retinal degeneration or obesity. They exhibit social interaction defects and stereotypical behaviors, linking CCDC28B to behavioral phenotypes without major structural cilia disruption. CRISPR/Cas9 knockout mouse, histological and cilia analysis, behavioral assays PLoS genetics Medium 35653384

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 217 16327777
2012 Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. Journal of medical genetics 94 22773737
2012 In search of triallelism in Bardet-Biedl syndrome. European journal of human genetics : EJHG 89 22353939
2006 Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Investigative ophthalmology & visual science 66 17065520
2020 Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders. Pediatric neurology 62 32139166
2016 Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression. Oncotarget 41 26701885
2021 Characterization of Organ-Specific Regulatory B Cells Using Single-Cell RNA Sequencing. Frontiers in immunology 39 34594327
2009 BBS7 and TTC8 (BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population. Human mutation 34 19402160
2012 Characterization of CCDC28B reveals its role in ciliogenesis and provides insight to understand its modifier effect on Bardet-Biedl syndrome. Human genetics 31 23015189
2013 The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. Human molecular genetics 28 23727834
2011 Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing. Ophthalmic genetics 26 22004009
2017 Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly. Journal of medical genetics 25 29127258
2018 Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B. Scientific reports 17 29445114
2021 A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly. Cell death and differentiation 6 34294890
2022 Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes. PLoS genetics 4 35653384
2024 CCDC28A deficiency causes head-tail coupling defects and immotility in murine spermatozoa. Scientific reports 3 39500989
2024 Tracing the pathways and mechanisms involved in medicinal uses of flaxseed with computational methods and bioinformatics tools. Frontiers in chemistry 2 38283897

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