Affinage

INVS

Inversin · UniProt Q9Y283

Length
1065 aa
Mass
117.8 kDa
Annotated
2026-04-28
26 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Inversin (INVS/NPHP2) is a ciliary scaffold protein that organizes a signaling module at the proximal 'Inversin compartment' of primary cilia, integrating nephrocystin complex assembly, planar cell polarity, and cilia maintenance. INVS directly interacts with NPHP1 and tubulin at cilia of renal tubular cells, and assembles a complex with ANKS6 and NEK8 kinase at the proximal cilium, where NEK8 acts downstream of INVS and the complex composition is regulated by HIF1AN-mediated hydroxylation (PMID:12872123, PMID:23793029). INVS inhibits Aurora A kinase activity, thereby suppressing HDAC6-dependent ciliary disassembly, and participates in planar cell polarity signaling through cooperation with Vangl2 and NPHP1 (PMID:24026243, PMID:37352572). Epithelial-specific loss of Invs in mice causes renal cyst formation and stromal fibrosis through cilia-dependent mechanisms, and mutations in INVS cause nephronophthisis (NPHP2) with aberrant Wnt/β-catenin signaling in human patients (PMID:36920028, PMID:20798123).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    The discovery that INVS physically interacts with NPHP1 and tubulin at primary cilia, and that its knockdown causes cystic kidneys and laterality defects, established inversin as a ciliary protein central to renal tubule integrity and left-right patterning.

    Evidence Reciprocal co-immunoprecipitation, immunofluorescence colocalization, and zebrafish morpholino knockdown

    PMID:12872123

    Open questions at the time
    • Binding interface between INVS and NPHP1 not mapped
    • Mechanism linking INVS loss to cystogenesis unknown
    • Whether INVS has enzymatic activity unresolved
  2. 2004 Medium

    Demonstrating that INVS forms a stable complex with polymerized tubulin and localizes to mitotic spindles revealed a dual role at both ciliary and cytoplasmic microtubule networks.

    Evidence Co-immunoprecipitation, co-pelleting with microtubules, colcemid/paclitaxel perturbation in renal epithelial cells

    PMID:15213257

    Open questions at the time
    • Functional significance of spindle localization not tested
    • Whether tubulin binding is direct or bridged by other factors unclear
  3. 2010 Low

    Analysis of a patient with a truncating INVS mutation linked inversin loss to upregulated canonical Wnt/β-catenin signaling in renal tissue, providing a candidate signaling mechanism for cystogenesis.

    Evidence Immunohistochemistry of β-catenin and Dishevelled-1 in patient kidney tissue

    PMID:20798123

    Open questions at the time
    • No functional rescue or direct manipulation of Wnt pathway performed
    • Single patient observation without mechanistic dissection
    • Causal direction between INVS loss and Wnt activation not established
  4. 2012 Medium

    Genetic epistasis in C. elegans and zebrafish established that NEK8 acts downstream of INVS in pronephros morphogenesis and defined the 'Inversin compartment' as a distinct ciliary subdomain requiring the EF-hand domain for targeting.

    Evidence Zebrafish morpholino knockdown with reciprocal mRNA rescue; C. elegans GFP localization and genetic epistasis

    PMID:22393243 PMID:22687244

    Open questions at the time
    • Direct biochemical mechanism of NEK8 activation by INVS unknown
    • Whether the Inversin compartment has a unique lipid or protein composition unresolved
  5. 2013 High

    Two parallel advances revealed that INVS inhibits Aurora A kinase to protect cilia from disassembly, and that ANKS6 bridges INVS to NEK8/NPHP3 in a proximal ciliary module regulated by HIF1AN hydroxylation, establishing inversin as both a signaling scaffold and a cilia stability factor.

    Evidence In vitro kinase assay and siRNA knockdown with pharmacological rescue in MDCK cells; reciprocal Co-IP, hydroxylation assay, and multi-organism epistasis

    PMID:23793029 PMID:24026243

    Open questions at the time
    • Hydroxylation sites on INVS and their functional consequences not fully characterized
    • How Aurora A inhibition and ANKS6 complex functions are coordinated unknown
  6. 2014 Medium

    Domain analysis in C. elegans and patient fibroblasts showed that the EF-hand and IQ domains are required for ciliary shaft localization of inversin, with truncation causing retention at the basal body.

    Evidence EF-hand domain deletion/mutagenesis with GFP localization and EM in C. elegans; immunofluorescence in patient fibroblasts with IQ1 truncation

    PMID:24677454 PMID:25501555

    Open questions at the time
    • Whether calcium binding to the EF-hand is dynamically regulated in vivo unknown
    • Transport mechanism from basal body to Inversin compartment not identified
  7. 2015 Medium

    Ultrastructural mapping placed the Inversin compartment at the proximal doublet microtubule region and revealed cell-type-specific ciliary targeting machinery for INVS.

    Evidence Electron microscopy and immunofluorescence in inv mutant mouse tracheal and renal cilia

    PMID:26615802

    Open questions at the time
    • Molecular identity of cell-type-specific targeting factors unknown
    • Functional consequence of INVS mislocalization in multiciliated cells not tested
  8. 2023 High

    Epithelial-specific Invs knockout demonstrated that cyst formation and fibrosis are epithelial-autonomous and partially cilia-dependent, resolving the tissue origin of inversin-mutant kidney disease, while genetic studies placed INVS in the Vangl2/PCP pathway during morphogenesis.

    Evidence Cell-type-specific Cre/loxP mouse knockouts with ciliogenesis epistasis; zebrafish invs mutant with vangl2/nphp1 morpholino knockdown

    PMID:36920028 PMID:37352572

    Open questions at the time
    • Signaling pathway linking cilia-dependent INVS function to fibrosis not defined
    • How INVS integrates PCP and Wnt signaling mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which INVS dimerization activates NEK8 kinase, and how the INVS–ANKS6–NEK8 module coordinates cilia stability, PCP signaling, and Wnt regulation in a unified pathway, remain to be resolved.
  • No structural model of the INVS–NEK8–ANKS6 complex exists
  • Direct substrates of activated NEK8 in the context of INVS signaling not identified
  • Whether INVS has intrinsic enzymatic or catalytic activity is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005929 cilium 5 GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
ANKS6AURKAHIF1ANNEK8NPHP1NPHP3VANGL2
Complex memberships
INVS-ANKS6-NEK8-NPHP3 moduleNPHP1-INVS complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Inversin (INVS/NPHP2) directly interacts with nephrocystin (NPHP1), and nephrocystin interacts with beta-tubulin; all three proteins colocalize to primary cilia of renal tubular cells. Knockdown of invs in zebrafish produces PKD-like renal cystic phenotype and randomization of heart looping. Co-immunoprecipitation, colocalization by immunofluorescence, zebrafish morpholino knockdown Nature genetics High 12872123
2004 Inversin forms a stable complex with tubulin in renal epithelial cells, localizes to ciliary, random, and polarized microtubule pools, is recruited to mitotic spindle fibers during cell division, and its microtubule association is dependent on tubulin polymerization state. Co-immunoprecipitation, co-pelleting assay, immunofluorescence, colcemid/paclitaxel treatment Journal of the American Society of Nephrology Medium 15213257
2013 NPHP2/Inversin directly interacts with Aurora A kinase, inhibits Aurora A phosphorylation/activation, and reduces its kinase activity in vitro, thereby interfering with HDAC6-mediated cilia disassembly. NPHP2 knockdown reduces cilia number in polarized MDCK cells, and Aurora A/HDAC6 inhibitors rescue this ciliogenesis defect. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown in MDCK cells, pharmacological rescue Nephrology, dialysis, transplantation Medium 24026243
2013 ANKS6 connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3 in a protein module localized to the proximal cilium. HIF1AN hydroxylates both ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 complex. NEK8 acts downstream of INVS in this module. Co-immunoprecipitation, zebrafish and Xenopus knockdown, hydroxylation assay, network analysis Nature genetics High 23793029
2012 In C. elegans, the inversin ortholog NPHP-2 localizes to the middle segment (Inversin compartment) of sensory cilia and is partially redundant with nphp-1 and nphp-4 for cilia placement. NPHP-2 genetically interacts with MKS ciliopathy gene orthologs to control cilia formation and placement, but is not required for correct localization of transition zone proteins or for IFT. GFP localization, genetic epistasis double mutants, RNAi knockdown in C. elegans Journal of cell science Medium 22393243
2012 In zebrafish, Nek8/Nphp9 acts downstream of Inv/Nphp2 during pronephros morphogenesis and left-right axis establishment, as nek8 mRNA rescued inv morphant phenotypes but inv mRNA could not rescue nek8 morphants; simultaneous knockdown was synergistically deleterious. Zebrafish morpholino knockdown, mRNA rescue epistasis experiments FEBS letters Medium 22687244
2014 In C. elegans, NPHP-2 (inversin ortholog) requires its calcium-binding EF hand domain for targeting to the Inversin compartment. The Inversin compartment (InvC) is distinct from the doublet microtubule region; nphp-2 and arl-13 define separate genetic modules that are both antagonized by hdac-6 and interact to regulate ciliogenesis, microtubule ultrastructure, and tubulin glutamylation. Domain deletion/mutagenesis of EF hand, GFP localization, genetic epistasis double mutants, electron microscopy in C. elegans PLoS genetics Medium 25501555
2015 The Inversin compartment in renal cilia corresponds structurally to the proximal microtubule doublet region of the ciliary axoneme. In inv mutant mice, Inv protein is retained at the basal body and not accumulated in the Inversin compartment of tracheal multiciliated cells, indicating cell-type-specific ciliary targeting machinery for Inversin. Electron microscopy, immunofluorescence in inv/nphp2 mutant mouse tissues, ciliary beating frequency measurement Cytoskeleton Medium 26615802
2010 An INVS truncation mutation (deleting the C-terminus) in human nephronophthisis is associated with abnormal expression of β-catenin and Dishevelled-1, indicating up-regulated canonical Wnt signaling in renal tubular cells. Immunohistochemistry of patient kidney tissue, genetic mutation analysis Nephrology, dialysis, transplantation Low 20798123
2023 Epithelial-specific knockout of Invs in mice causes renal cyst formation and severe stromal fibrosis via epithelial-stromal crosstalk, while stromal-specific Invs deletion has no observable phenotype; concomitant removal of cilia (ciliogenesis genes) partially suppresses Invs mutant kidney phenotypes, demonstrating that inversin function depends on intact cilia in vivo. Cell-type-specific Cre/loxP mouse knockouts, genetic interaction with ciliogenesis mutants, histology, EdU/BrdU proliferation assays eLife High 36920028
2014 A truncating mutation in the IQ1 domain of inversin causes its mislocalization: in patient fibroblasts, mutant inversin is detected only at the basal body and not in the ciliary axoneme, demonstrating that the IQ1 domain (or an intact C-terminus) is required for axonemal/ciliary shaft localization of inversin. Immunofluorescence localization in patient-derived fibroblasts, nonsense-mediated decay analysis, exome sequencing American journal of medical genetics Part A Medium 24677454
2023 Inversin (NPHP2) cooperates with Vangl2 and NPHP1 in planar cell polarity (PCP) signaling during zebrafish cloaca formation; simultaneous depletion of nphp1 and vangl2 in invs mutant zebrafish caused pronounced cloaca malformations with reduced apoptotic activity, placing NPHP2 in the PCP pathway with Vangl2. Zebrafish invs mutant line, morpholino knockdown, time-lapse imaging, in situ hybridization, apoptosis assay Biochemical and biophysical research communications Medium 37352572
2024 In C. elegans, the Inversin complex (composed of MLT-4/INVS, NEKL-2/NEK8) is activated by dimerization: forced dimerization of MLT-4 or NEKL-2 via optogenetics or fluorescent tag-induced dimerization recapitulates a constitutively active gain-of-function phenotype, and monomerization suppresses it; dimerization of NEKL-2 bypasses loss of MLT-4, placing INVS upstream of NEK8 kinase activation. Genome engineering of fluorescent tags, optogenetics-induced dimerization, genetic suppressor analysis in C. elegans bioRxivpreprint Medium bio_10.1101_2024.05.17.594761

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nature genetics 496 12872123
2013 ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature genetics 170 23793029
2009 Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. Kidney international 87 19177160
2011 Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 51 22076433
2012 Ciliogenesis in Caenorhabditis elegans requires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins. Journal of cell science 42 22393243
2004 The Invs gene encodes a microtubule-associated protein. Journal of the American Society of Nephrology : JASN 34 15213257
2014 The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans. PLoS genetics 32 25501555
2006 Retinitis pigmentosa and renal failure in a patient with mutations in INVS. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 28 16522655
2013 The nephronophthisis gene product NPHP2/Inversin interacts with Aurora A and interferes with HDAC6-mediated cilia disassembly. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 27 24026243
2010 A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 26 20798123
2013 Broadening the ciliopathy spectrum: motile cilia dyskinesia, and nephronophthisis associated with a previously unreported homozygous mutation in the INVS/NPHP2 gene. American journal of medical genetics. Part A 23 23713026
2016 Identification of the invertase gene family (INVs) in tea plant and their expression analysis under abiotic stress. Plant cell reports 21 27538912
2012 The ciliary protein Nek8/Nphp9 acts downstream of Inv/Nphp2 during pronephros morphogenesis and left-right establishment in zebrafish. FEBS letters 19 22687244
2017 InvS Coordinates Expression of PrgH and FimZ and Is Required for Invasion of Epithelial Cells by Salmonella enterica serovar Typhimurium. Journal of bacteriology 16 28439039
2008 Association of INVS (NPHP2) mutation in an adolescent exhibiting nephronophthisis (NPH) and complete situs inversus. Clinical nephrology 12 18218308
2005 Differential tissue distribution of the Invs gene product inversin. Cell and tissue research 11 16007506
2015 Structural basis of the Inv compartment and ciliary abnormalities in Inv/nphp2 mutant mice. Cytoskeleton (Hoboken, N.J.) 8 26615802
2023 Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse. eLife 7 36920028
2014 Early presentation of cystic kidneys in a family with a homozygous INVS mutation. American journal of medical genetics. Part A 7 24677454
2004 Analysis of multiple Invs transcripts in mouse and MDCK cells. Genomics 5 15533716
2023 Inversin (NPHP2) and Vangl2 are required for normal zebrafish cloaca formation. Biochemical and biophysical research communications 3 37352572
2019 Novel splice site and nonsense variants in INVS cause infantile nephronophthisis. Gene 2 31706999
2018 Tubular cell loss in early inv/nphp2 mutant kidneys represents a possible homeostatic mechanism in cortical tubular formation. PloS one 2 29889867
2024 INVS Mutation-Related NPHP2 Nephronophthisis With Glomerulocystic Disease: A Case Report. Kidney medicine 1 40475304
2007 Lack of NPHP2 mutations in a newborn infant with Joubert syndrome-related disorder presenting as end-stage renal disease. Pediatric nephrology (Berlin, Germany) 1 17216245
2026 Bio-Inspired lipid nanovesicles (iNVs) incorporating membrane proteins from healthy tendon stem cells for targeted protein restoration in tendinopathic in vitro model. Artificial cells, nanomedicine, and biotechnology 0 41604518