Affinage

DYNC1I2

Cytoplasmic dynein 1 intermediate chain 2 · UniProt Q13409

Round 2 corrected
Length
638 aa
Mass
71.5 kDa
Annotated
2026-04-28
42 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DYNC1I2 is a core intermediate chain subunit of the cytoplasmic dynein-1 complex that bridges the motor to its cargoes and regulatory partners, directly binding the p150Glued subunit of dynactin through its N-terminal domain to enable dynactin-dependent processive minus-end-directed motility (PMID:8522607, PMID:24986880). The gene undergoes extensive alternative splicing—maximal in the nervous system—generating tissue-specific isoforms that equip distinct dynein complexes for specialized functions, and it is broadly expressed throughout the developing CNS and PNS (PMID:10049579, PMID:20657784). DYNC1I2 is phosphorylated by ERK on a conserved serine near the dynactin-binding site (without disrupting p150Glued interaction), interacts with TMEM39A to maintain perinuclear lysosome positioning and mTOR signaling, and its mRNA is stabilized by the lncRNA HHIP-AS1 competing with miR-425-5p (PMID:23434660, PMID:33531362, PMID:35831316). Bi-allelic loss-of-function variants cause autosomal-recessive syndromic microcephaly with intellectual disability, linked to defective mitotic spindle integrity and increased apoptosis during neurogenesis (PMID:31079899).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1995 High

    Establishing how cytoplasmic dynein physically engages dynactin resolved a central question about cargo attachment: the N-terminal region of the dynein intermediate chains (including DYNC1I2) directly binds p150Glued, defining the intermediate chain as the primary dynein–dynactin interface.

    Evidence Blot overlay and co-immunoprecipitation from rat brain cytosol with truncation mutant mapping

    PMID:8522607

    Open questions at the time
    • Whether phosphorylation or splicing near the binding site modulates the interaction was unknown
    • Functional consequence of dynactin binding on motor processivity not yet tested
  2. 1999 Medium

    Determining tissue expression patterns revealed that DYNC1I2, unlike its paralog DYNC1I1, is expressed broadly throughout the embryonic CNS and PNS, indicating non-redundant developmental roles for the two intermediate chain genes.

    Evidence RNA in situ hybridization during mouse embryogenesis

    PMID:10049579

    Open questions at the time
    • Functional consequences of paralog-specific expression were not tested
    • Protein-level validation across tissues was not performed
  3. 2001 Medium

    Linking dynein intermediate chains to steroid receptor nuclear import showed that DYNC1I2-containing dynein serves as a transport motor for the glucocorticoid receptor via the Hsp90-FKBP52 complex, broadening its known cargo repertoire.

    Evidence Co-immunoprecipitation and subcellular fractionation with GR translocation readout

    PMID:11751894

    Open questions at the time
    • Direct binding between DYNC1I2 and FKBP52 was not mapped at residue resolution
    • Contribution of DYNC1I2 vs. DYNC1I1 to GR transport was not distinguished
  4. 2010 Medium

    Systematic cataloguing of DYNC1I2 splice isoforms revealed maximum diversity in neurons, with novel exons and promoters, establishing that alternative splicing generates functionally distinct dynein complexes in a tissue-specific manner.

    Evidence RT-PCR isoform profiling across mouse, rat, and human tissues with bioinformatic orthology analysis

    PMID:20657784

    Open questions at the time
    • Functional differences between individual splice isoforms in cargo specificity remain untested
    • Structural consequences of alternative exon inclusion not resolved
  5. 2013 Medium

    Identifying ERK-mediated phosphorylation of DYNC1I2 on a conserved serine near the p150Glued-binding site—without disrupting dynactin interaction—revealed a signaling input that regulates dynein through a dynactin-independent mechanism.

    Evidence In vitro kinase assay with phosphomimetic mutagenesis and co-immunoprecipitation after EGF stimulation

    PMID:23434660

    Open questions at the time
    • Downstream functional output of ERK phosphorylation (cargo transport, motility) was not characterized
    • In vivo confirmation of this phosphosite's role is lacking
  6. 2014 High

    Reconstituting a fully recombinant human dynein complex (incorporating DYNC1I2) demonstrated that dynein alone is non-processive; dynactin plus BICD2 converts it into a processive minus-end motor, defining the activation mechanism.

    Evidence Baculovirus-expressed recombinant complex, single-molecule fluorescence microscopy, negative stain EM

    PMID:24986880

    Open questions at the time
    • Specific contribution of DYNC1I2 vs. DYNC1I1 to complex assembly and processivity not dissected
    • Role of intermediate chain phosphorylation or splice variants in activation was not tested
  7. 2019 High

    Discovery that bi-allelic DYNC1I2 loss-of-function variants cause syndromic microcephaly established DYNC1I2 as essential for mitotic spindle integrity during neurogenesis, with prolonged mitosis and apoptosis as the cellular mechanism.

    Evidence Whole-exome sequencing of three pedigrees, CRISPR-Cas9 and morpholino zebrafish models, complementation assay with patient variant

    PMID:31079899

    Open questions at the time
    • How DYNC1I2 specifically maintains spindle pole integrity at the molecular level is unresolved
    • Whether partial loss of function produces milder neurological phenotypes is unknown
  8. 2021 Medium

    Identifying TMEM39A as a physical partner of DYNC1I2 that maintains perinuclear lysosome positioning connected dynein intermediate chain function to organelle distribution and mTOR signaling.

    Evidence Co-immunoprecipitation in mammalian cells plus genetic epistasis with lysosome and mTOR/HLH-30 readouts in C. elegans

    PMID:33531362

    Open questions at the time
    • Binding interface between TMEM39A and DYNC1I2 is unmapped
    • Whether TMEM39A serves as a dynein cargo adaptor or allosteric regulator is not distinguished
  9. 2022 Medium

    Demonstrating that the lncRNA HHIP-AS1 stabilizes DYNC1I2 mRNA by sequestering miR-425-5p revealed a post-transcriptional control mechanism that tunes DYNC1I2 protein levels and mitotic spindle fidelity in SHH-driven tumors.

    Evidence RNA immunoprecipitation for lncRNA–mRNA binding, miRNA target assay, knockdown with spindle and xenograft readouts

    PMID:35831316

    Open questions at the time
    • Whether this regulatory axis operates in normal neural development is unknown
    • Other miRNAs or RNA-binding proteins that regulate DYNC1I2 are not surveyed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include how individual DYNC1I2 splice isoforms specify cargo selectivity, what the structural basis of ERK-phosphorylation-mediated regulation is, and whether DYNC1I2 contributes distinctly to dynein-2 or other non-canonical dynein functions.
  • No isoform-specific cargo reconstitution has been performed
  • Structural model of phosphorylated DYNC1I2 within the dynein–dynactin supercomplex is lacking
  • Genotype–phenotype spectrum for partial DYNC1I2 loss in humans is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9609507 Protein localization 2 GO:0005764 lysosome 1
Partners
BICD2DCTN1FKBP4HSP90AA1TMEM39A
Complex memberships
Cytoplasmic dynein-1 complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Cytoplasmic dynein intermediate chains (including IC-1A/DYNC1I1 and the IC-2/DYNC1I2 isoform tested) directly bind the p150Glued subunit of the dynactin complex. Using blot overlay and immunoprecipitation assays, the interaction was mapped to amino acids 1–123 of IC-1A and amino acids 200–811 of p150Glued, establishing dynactin as a specific receptor/adaptor for dynein via the intermediate chains. Blot overlay assay, co-immunoprecipitation from rat brain cytosol and membranes, truncation mutant mapping The Journal of cell biology High 8522607
1999 Mouse Dync1i2 (Dnci2) displays broad expression throughout the entire central nervous system and most of the peripheral nervous system during embryogenesis, with a dynamic expression profile in the developing limb bud, in contrast to the highly restricted forebrain/PNS expression of Dync1i1, indicating distinct tissue-specific roles for the two intermediate chain paralogs. RNA in situ hybridization during mouse embryogenesis Genomics Medium 10049579
2001 Hormone-bound glucocorticoid receptor (GR) recruits dynein to an Hsp90-FKBP52-dynein complex (via FKBP52 substitution for FKBP51), and this complex undergoes dynein-mediated retrograde transport from cytoplasm to nucleus. The dynein intermediate chains participate in this cargo-binding interaction, linking cytoplasmic dynein to steroid receptor nuclear trafficking. Immunofluorescence, subcellular fractionation, co-immunoprecipitation The Journal of biological chemistry Medium 11751894
2010 A systematic survey of mouse Dync1i2 mRNA revealed a complex pattern of alternative splicing, with maximum isoform diversity in the embryonic and adult nervous system. Novel transcripts were identified, including a new promoter and alternative non-coding exon 1 for Dync1i2, with orthologues in human and rat. Different splice isoforms of each intermediate chain are essential for the function of distinct dynein complexes in neurons. RT-PCR, bioinformatics analysis of mouse/rat/human genomic and cDNA sequences, tissue mRNA expression profiling PloS one Medium 20657784
2013 EGF receptor stimulation activates ERK, which phosphorylates DYNC1I2 (IC-2) on a novel, highly conserved serine residue proximal to the p150Glued binding site. Phosphomimetic substitution of this serine does not impair p150Glued binding, suggesting ERK phosphorylation of IC-2 regulates dynein function through mechanisms independent of dynactin interaction. Affinity purification, in vitro kinase assay, site-directed mutagenesis (phosphomimetic), co-immunoprecipitation International journal of molecular sciences Medium 23434660
2014 Fully recombinant human cytoplasmic dynein complex (containing DYNC1I2 among its subunits) was reconstituted in insect cells and shown to be non-processive alone in vitro; addition of dynactin together with the N-terminal cargo adaptor domain of BICD2 converts the complex into a highly processive, unidirectional minus-end motor. Negative stain EM shows dynactin positioned along the dynein tail in this activated complex. Baculovirus-mediated recombinant complex reconstitution, single-molecule fluorescence microscopy, negative stain electron microscopy The EMBO journal High 24986880
2019 Bi-allelic loss-of-function variants in DYNC1I2 cause autosomal-recessive syndromic microcephaly with intellectual disability and cerebral malformations. CRISPR-Cas9 disruption or morpholino knockdown of dync1i2a in zebrafish larvae caused craniofacial patterning defects and reduced head size, associated with increased apoptosis and prolonged mitosis due to abnormal mitotic spindle morphology. The p.Tyr247Cys variant attenuates gene function as shown by complementation assays, implicating DYNC1I2 in mitotic spindle integrity during neurogenesis. Whole-exome sequencing, homozygosity mapping, CRISPR-Cas9 zebrafish knockout, morpholino knockdown, cell cycle and apoptosis analysis, complementation assay, protein structural analysis American journal of human genetics High 31079899
2021 TMEM39A (and its C. elegans ortholog TMEM-39) physically interacts with DYNC1I2 (dynein intermediate light chain) to maintain proper lysosome distribution in the perinuclear region. Loss of TMEM39A causes lysosome redistribution to the cell periphery in mammalian cells; loss of the DYNC1I2 homolog in C. elegans similarly impairs lysosome distribution and mTOR signaling, activating the TFEB-like transcription factor HLH-30. Co-immunoprecipitation (TMEM39A–DYNC1I2 interaction), live-cell imaging of lysosome dynamics, genetic epistasis in C. elegans (tmem-39 and dync1i2 homolog mutants), mTOR/HLH-30 signaling readouts Proceedings of the National Academy of Sciences of the United States of America Medium 33531362
2022 The primate-specific lncRNA HHIP-AS1 directly binds the mRNA of DYNC1I2 and protects it from degradation by hsa-miR-425-5p. Knockdown of HHIP-AS1 reduces DYNC1I2 protein levels, induces mitotic spindle deregulation, and impairs tumorigenicity in vitro and in vivo, identifying a post-transcriptional regulatory mechanism controlling DYNC1I2 abundance in SHH-driven tumors. RNA immunoprecipitation (lncRNA–mRNA binding), miRNA target assay, HHIP-AS1 knockdown with mitotic spindle and tumorigenicity readouts (in vitro and in vivo xenograft) Nature communications Medium 35831316
2026 In a diabetic peripheral neuropathy rat model, alpha-lipoic acid (ALA) downregulates DYNC1I2 expression in sciatic nerve while upregulating the anterograde motor KIF5A, and activates AMPK/CREB signaling. This suggests DYNC1I2-mediated retrograde mitochondrial axonal transport is modulated by the AMPK/CREB pathway, and its reduction by ALA promotes net anterograde mitochondrial movement to protect neurons. Western blotting, immunofluorescence, nerve conduction velocity measurement, STZ-induced diabetic rat model, NSC34 cell culture model PloS one Low 41920893

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1995 Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. The Journal of cell biology 427 7790358
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1995 Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued. The Journal of cell biology 400 8522607
2001 A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. The Journal of biological chemistry 348 11751894
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2014 In vitro reconstitution of a highly processive recombinant human dynein complex. The EMBO journal 289 24986880
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2004 From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. Cancer research 72 15520179
2010 Mouse cytoplasmic dynein intermediate chains: identification of new isoforms, alternative splicing and tissue distribution of transcripts. PloS one 35 20657784
1999 Cloning and characterization of two cytoplasmic dynein intermediate chain genes in mouse and human. Genomics 34 10049579
2022 The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors. Nature communications 26 35831316
2019 Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features. American journal of human genetics 24 31079899
2014 Proteomic analysis of the action of the Mycobacterium ulcerans toxin mycolactone: targeting host cells cytoskeleton and collagen. PLoS neglected tropical diseases 23 25101965
2021 The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics. Proceedings of the National Academy of Sciences of the United States of America 7 33531362
2013 Epidermal growth factor stimulates extracellular-signal regulated kinase phosphorylation of a novel site on cytoplasmic Dynein intermediate chain 2. International journal of molecular sciences 7 23434660
2021 Copy number variation of bovine DYNC1I2 gene is associated with body conformation traits in chinese beef cattle. Gene 6 34740731
2023 Single-Locus and Multi-Locus Genome-Wide Association Studies Identify Genes Associated with Liver Cu Concentration in Merinoland Sheep. Genes 4 37239413
2024 Tislelizumab plus nimotuzumab is effective against recurrent or metastatic oral squamous cell carcinoma among patients with a performance status score ≥ 2: a retrospective study. Frontiers in oncology 3 38293699
2026 Effect of ALA on preventing diabetic peripheral neuropathy in rats through mitochondrial axonal transport. PloS one 0 41920893