Affinage

DRC4

Dynein regulatory complex subunit 4 · UniProt O95995

Length
478 aa
Mass
56.4 kDa
Annotated
2026-06-09
26 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DRC4/GAS8 is a subunit of the axonemal nexin-dynein regulatory complex (N-DRC) that provides a direct molecular linkage between the regulatory complex and the microtubule lattice of motile cilia and flagella (PMID:17366626, PMID:27120127). It binds microtubules directly in vitro and in vivo through a discrete microtubule-binding domain (GMAD), with an internal region (IMAD) attenuating this interaction in cis or trans (PMID:17366626). Within the axoneme, DRC4/GAS8 is required for N-DRC integrity and for proper subcellular localization of the partner subunit DRC3, while being dispensable for CCDC39 and CCDC40 expression (PMID:27120127); it is delivered into flagella by intraflagellar transport on trains largely separate from those carrying DRC2, indicating stepwise assembly of the N-DRC on the axoneme (PMID:36598807). It physically associates with the N-DRC component ANKRD5 independently of calcium regulation [PMID:bio_10.1101_2024.12.03.626701]. Bi-allelic loss-of-function mutations in GAS8 cause primary ciliary dyskinesia with axonemal microtubule disorganization (PMID:27120127), and loss of GAS8 from sperm flagella produces peripheral doublet misalignment and a multiple morphological abnormalities of the flagella phenotype underlying male infertility (PMID:37950557). Beyond its axonemal role, DRC4/GAS8 associates with the pericentrosomal Golgi apparatus in non-ciliated cells in a microtubule-dependent, cell-cycle-regulated manner (PMID:16643277), interacts specifically with GTP-bound Rab3B at the Golgi (PMID:18396146), and modulates Smoothened ciliary localization and Hedgehog signaling through its C-terminus in a GRK2-dependent fashion (PMID:21659505).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Establishing where Gas8 acts: its localization to motile-ciliated and flagellar structures pointed to a role in the motility apparatus rather than a generic cytoplasmic function.

    Evidence Northern blotting and immunohistochemistry across murine sperm, bronchial, and fallopian tube epithelia with post-meiotic expression regulation

    PMID:11751847

    Open questions at the time
    • Localization alone did not define a molecular activity
    • No interacting partners or complex membership identified
  2. 2006 Medium

    Revealed a non-axonemal pool of DRC4 at the pericentrosomal Golgi in cells lacking motile cilia, raising the question of a broader microtubule-dependent function.

    Evidence Immunofluorescence, subcellular fractionation, BFA and microtubule-depolymerization perturbations, and in vitro Golgi membrane binding in mammalian cells

    PMID:16643277

    Open questions at the time
    • Functional consequence of Golgi association not defined
    • Relationship between Golgi pool and ciliary pool unclear
  3. 2007 High

    Defined the molecular basis for linking the dynein regulatory complex to the axoneme by mapping a direct microtubule-binding domain.

    Evidence In vitro microtubule co-sedimentation, deletion/domain mapping (GMAD and IMAD), single-particle binding, and in vivo localization

    PMID:17366626

    Open questions at the time
    • Did not place DRC4 within the assembled N-DRC structurally
    • Regulation of the IMAD attenuation in vivo not resolved
  4. 2008 Medium

    Identified a nucleotide-state-specific partner, GTP-bound Rab3B, connecting the Golgi-associated DRC4 pool to a small GTPase.

    Evidence Yeast two-hybrid, co-localization, GTP/GDP specificity assay, and Rab3B-binding-domain relocation in NIH 3T3 cells

    PMID:18396146

    Open questions at the time
    • Downstream consequence of the Rab3B interaction unknown
    • Y2H interaction not validated by reciprocal endogenous Co-IP
  5. 2011 High

    Linked DRC4 to ciliary signaling by showing its C-terminus controls Smoothened ciliary localization and Hedgehog output via GRK2.

    Evidence Co-IP, siRNA knockdown and overexpression in ciliated cells, plus zebrafish morpholino knockdown with Gli/GRK2 epistasis

    PMID:21659505

    Open questions at the time
    • Mechanism by which DRC4 cooperates with GRK2 not detailed
    • Connection between signaling role and N-DRC motility role unresolved
  6. 2016 High

    Demonstrated DRC4/GAS8 is causally required for human motile cilia function and for organizing other N-DRC subunits.

    Evidence Whole exome sequencing, high-speed videomicroscopy, and immunofluorescence on patient respiratory cilia showing DRC3 mislocalization

    PMID:27120127

    Open questions at the time
    • Order of subunit assembly within the complex not established
    • Whether DRC3 mislocalization is direct or secondary not resolved
  7. 2023 High

    Showed how N-DRC subunits reach the axoneme, establishing that DRC2 and DRC4 are transported independently by IFT and assemble stepwise.

    Evidence In vivo fluorescence and dual-color IFT imaging of tagged DRC2 and DRC4 with reciprocal mutant rescue in Chlamydomonas

    PMID:36598807

    Open questions at the time
    • Adaptors coupling DRC4 to IFT trains not identified
    • Sequence of incorporation steps at the axoneme not fully mapped
  8. 2023 Medium

    Confirmed GAS8 is essential for sperm axoneme integrity, with loss producing doublet misalignment and male infertility distinct from full PCD.

    Evidence Whole exome sequencing, immunofluorescence on patient spermatozoa, and transmission electron microscopy

    PMID:37950557

    Open questions at the time
    • Single case limits genotype-phenotype generalization
    • Why phenotype is flagellum-restricted versus systemic PCD unexplained
  9. 2024 Medium

    Extended the N-DRC interaction map by identifying ANKRD5 as a calcium-independent physical partner of DRC4.

    Evidence Co-IP of ANKRD5 with DRC4/GAS8, Ankrd5 knockout mouse, and cryo-electron tomography of sperm axoneme (preprint)

    PMID:bio_10.1101_2024.12.03.626701

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Structural position of DRC4-ANKRD5 contact within the N-DRC not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the axonemal N-DRC role of DRC4 mechanistically relates to its Golgi/Rab3B association and Hedgehog signaling functions remains unresolved.
  • No unifying model linking the structural and signaling roles
  • Regulation of partitioning between axonemal and Golgi pools unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005794 Golgi apparatus 2 GO:0005929 cilium 2 GO:0005815 microtubule organizing center 1 GO:0005856 cytoskeleton 1
Pathway
GO:0005929 cilium 1 R-HSA-162582 Signal Transduction 1
Partners
ANKRD5DRC2DRC3GRK2RAB3BSMOTCTE1
Complex memberships
nexin-dynein regulatory complex (N-DRC)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Gas8 protein is localized to sperm flagella, cilia of bronchial epithelial cells, and fallopian tube epithelial cells, with expression regulated post-meiotically during spermatogenesis; its spatial association with the sperm motility apparatus suggests a role in sperm motility. Northern blotting, immunohistochemistry, subcellular localization in murine tissues The Journal of biological chemistry Medium 11751847
2006 GAS11 (DRC4) is associated with the pericentrosomal Golgi apparatus in mammalian cells lacking motile cilia; this localization depends on intact microtubules, is cell-cycle regulated (dispersed during mitosis), and recombinant GAS11 binds Golgi membranes in vitro. In growth-arrested cells, GAS11 co-localizes with γ-tubulin at the base of the primary cilium. Immunofluorescence, subcellular fractionation, brefeldin A and microtubule depolymerization treatments, in vitro Golgi membrane binding assay Traffic (Copenhagen, Denmark) Medium 16643277
2007 Gas11 (DRC4) directly binds microtubules in vitro and in vivo via a novel microtubule-binding domain (GMAD); a distinct internal region (IMAD) attenuates this interaction and can act in cis or trans, providing a direct molecular linkage for the dynein regulatory complex to axonemal microtubules. In vitro microtubule co-sedimentation, deletion analysis, single-particle binding assays, in vivo localization Cell motility and the cytoskeleton High 17366626
2008 Gas8 (DRC4) interacts specifically with the GTP-bound form of Rab3B at the Golgi apparatus in NIH 3T3 cells, co-localizing with Rab3B at the Golgi; the Rab3B-binding domain of Gas8 is sufficient to relocate Rab3B. Yeast two-hybrid, co-localization by immunofluorescence, GTP/GDP-binding specificity assay, dominant-negative domain expression Archives of biochemistry and biophysics Medium 18396146
2011 Gas8 (DRC4) interacts with Smoothened (Smo) via its C-terminus to modulate Smo ciliary localization and Hedgehog signaling; Gas8 knockdown reduces Smo ciliary localization and signaling activity, while overexpression stimulates Smo activity in a GRK2-dependent manner. In zebrafish, Gas8 knockdown attenuates Hedgehog transcriptional responses and impairs early muscle development, rescued by Gas8 mRNA or constitutively active Gli. Co-immunoprecipitation, siRNA knockdown, overexpression in ciliated cells, zebrafish morpholino knockdown, epistasis with Gli/GRK2 The Journal of biological chemistry High 21659505
2016 Bi-allelic loss-of-function mutations in GAS8 (DRC4) cause primary ciliary dyskinesia with axonemal microtubule disorganization; GAS8 is required for proper subcellular localization of another N-DRC subunit DRC3 in respiratory cilia, but not for expression of CCDC39 or CCDC40. Whole exome sequencing, Sanger validation, high-speed videomicroscopy, immunofluorescence on patient respiratory cilia Human mutation High 27120127
2023 DRC2 and DRC4 are transported independently into flagella via intraflagellar transport (IFT) trains; tagged DRC2 undergoes IFT in mutants lacking DRC4 and vice versa, and simultaneous imaging shows they travel mostly on separate trains with only occasional co-transport, indicating the N-DRC assembles stepwise on the axoneme. In vivo fluorescence imaging of tagged DRC2 and DRC4 in Chlamydomonas reinhardtii, mutant rescue experiments, simultaneous dual-color IFT imaging Molecular biology of the cell High 36598807
2023 A homozygous GAS8 splice donor variant causes loss of GAS8 protein from sperm flagella (confirmed by absent immunofluorescence signal) and leads to peripheral microtubule doublet misalignment (MMAF phenotype) without full PCD symptoms, confirming GAS8's essential role in N-DRC integrity of sperm axoneme. Whole exome sequencing, immunofluorescence on patient spermatozoa, transmission electron microscopy Clinical genetics Medium 37950557
2024 ANKRD5 physically interacts with DRC4/GAS8 (and DRC5/TCTE1) as part of the N-DRC; these interactions occur independently of calcium regulation and ANKRD5 deficiency in mice results in impaired sperm motility with increased structural heterogeneity of doublet microtubules under mechanical stress. Co-immunoprecipitation (ANKRD5 with DRC4/GAS8), Ankrd5 knockout mouse model, cryo-electron tomography of sperm axoneme bioRxivpreprint Medium bio_10.1101_2024.12.03.626701

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations. Human molecular genetics 73 26941397
2018 LncRNA GAS8-AS1 inhibits cell proliferation through ATG5-mediated autophagy in papillary thyroid cancer. Endocrine 53 29327301
2016 Mutations in GAS8, a Gene Encoding a Nexin-Dynein Regulatory Complex Subunit, Cause Primary Ciliary Dyskinesia with Axonemal Disorganization. Human mutation 47 27120127
1998 Characterization and screening for mutations of the growth arrest-specific 11 (GAS11) and C16orf3 genes at 16q24.3 in breast cancer. Genomics 45 9790751
2018 The long noncoding RNA GAS8-AS1 suppresses hepatocarcinogenesis by epigenetically activating the tumor suppressor GAS8. The Journal of biological chemistry 42 30228180
2017 Plasma lncRNA GAS8-AS1 as a Potential Biomarker of Papillary Thyroid Carcinoma in Chinese Patients. International journal of endocrinology 39 28781594
2020 ATF2-Induced lncRNA GAS8-AS1 Promotes Autophagy of Thyroid Cancer Cells by Targeting the miR-187-3p/ATG5 and miR-1343-3p/ATG7 Axes. Molecular therapy. Nucleic acids 32 33230459
2011 Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling. The Journal of biological chemistry 28 21659505
2002 Isolation and properties of Gas8, a growth arrest-specific gene regulated during male gametogenesis to produce a protein associated with the sperm motility apparatus. The Journal of biological chemistry 28 11751847
2019 LncRNA GAS8-AS1 suppresses papillary thyroid carcinoma cell growth through the miR-135b-5p/CCND2 axis. Bioscience reports 26 30429236
2019 LncRNA GAS8-AS inhibits colorectal cancer (CRC) cell proliferation by downregulating lncRNA AFAP1-AS1. Gene 23 31132513
2007 Direct interaction of Gas11 with microtubules: implications for the dynein regulatory complex. Cell motility and the cytoskeleton 19 17366626
2020 LncRNA GAS8-AS1 Inhibits Ovarian Cancer Progression Through Activating Beclin1-Mediated Autophagy. OncoTargets and therapy 18 33116622
2006 Expanding the role of the dynein regulatory complex to non-axonemal functions: association of GAS11 with the Golgi apparatus. Traffic (Copenhagen, Denmark) 17 16643277
2021 LncRNA GAS8-AS1 downregulates lncRNA NEAT1 to inhibit glioblastoma cell proliferation. Brain and behavior 15 33942556
2020 lncRNA GAS8-AS1 downregulates lncRNA UCA1 to inhibit osteosarcoma cell migration and invasion. Journal of orthopaedic surgery and research 15 32013985
2019 GAS8 and its naturally occurring antisense RNA as biomarkers in multiple sclerosis. Immunobiology 11 31003831
2021 Long noncoding RNA GAS8-AS1: A novel biomarker in human diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 10 33838502
2008 Interaction of Rab3B with microtubule-binding protein Gas8 in NIH 3T3 cells. Archives of biochemistry and biophysics 10 18396146
2023 In vivo imaging reveals independent intraflagellar transport of the nexin-dynein regulatory complex subunits DRC2 and DRC4. Molecular biology of the cell 7 36598807
2023 A splice donor variant of GAS8 induces structural disorganization of the axoneme in sperm flagella and leads to nonsyndromic male infertility. Clinical genetics 6 37950557
2019 GAS8 and GAS8-AS1 expression in gastric cancer. Gastroenterology and hepatology from bed to bench 5 31749921
2020 lncRNA GAS8-AS1 genetic alterations in papillary thyroid carcinoma and their clinical significance. Cancer biomarkers : section A of Disease markers 3 32675393
2025 The expression of the lncRNAs USP30-AS1, ELFN1-AS1, GAS8-AS1, and SNHG11 in breast cancer samples from Iranian patients from 2014 to 2019: a cross-sectional study. BMC research notes 2 39757210
2024 LncRNA GAS8-AS1 dinucleotide genetic variantn.713A>G, n.714T>C is associated with early-stage disease, lymph node, and distant metastasis in differentiated thyroid cancer. Endocrine 1 38580894
2024 A novel mutation in GAS8 gene associated with chronic rhinosinusitis with nasal polyposis in a case of primary ciliary dyskinesia: a case report. Frontiers in pediatrics 1 38873586

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