Affinage

INVS

Inversin · UniProt Q9Y283

Length
1065 aa
Mass
117.8 kDa
Annotated
2026-06-10
26 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Inversin (INVS/NPHP2) is a ciliary scaffold protein that organizes a proximal compartment of primary and motile cilia and links ciliary architecture to renal epithelial homeostasis (PMID:12872123, PMID:22393243). It binds tubulin and associates with ciliary, cytoplasmic, and mitotic-spindle microtubule pools in a polymerization-dependent manner (PMID:15213257), and its EF-hand domain targets it to the microtubule-doublet 'Inversin compartment' of the cilium, while loss of distal motifs by mutation restricts the protein to the basal body and abolishes axonemal targeting (PMID:25501555, PMID:26615802, PMID:24677454). Within this compartment, inversin nucleates a proximal-cilium module in which ANKS6 bridges NEK8 to INVS and NPHP3, a complex whose composition is tuned by HIF1AN-mediated hydroxylation of both ANKS6 and INVS, placing the assembly downstream of oxygen sensing; NEK8 acts genetically downstream of inversin in left-right axis and pronephros morphogenesis (PMID:22687244, PMID:23793029). Inversin also restrains ciliary turnover by directly binding and inhibiting Aurora A kinase, thereby blocking HDAC6-dependent cilia disassembly (PMID:24026243). Functionally, inversin participates in planar cell polarity signaling together with NPHP1 and Vangl2 (PMID:37352572), and its epithelial-cell-autonomous loss drives renal cyst formation and stromal fibrosis through cilia-dependent mechanisms, with the fibrotic and cystic components separable into p38 MAPK- and MEK/ERK-regulated arms (PMID:22076433, PMID:36920028). A truncating IQ-domain mutation linking INVS to human cystic kidney disease produces the same axonemal-targeting defect seen in disease fibroblasts (PMID:24677454).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established inversin as a ciliary protein physically partnered with nephrocystin, connecting the gene to nephronophthisis biology and laterality determination rather than leaving it an orphan locus.

    Evidence Co-IP, immunofluorescence colocalization with beta-tubulin, and zebrafish morpholino knockdown

    PMID:12872123

    Open questions at the time
    • Did not define the molecular activity of inversin within the cilium
    • Did not map the interaction interface with NPHP1
  2. 2004 Medium

    Showed inversin is a microtubule-associated protein spanning ciliary, cytoplasmic, and mitotic-spindle tubulin pools, framing it as a cytoskeletal scaffold rather than a cilium-exclusive factor.

    Evidence Co-IP, co-pelleting assay, immunofluorescence, and microtubule depolymerization pharmacology in renal epithelial cells

    PMID:15213257

    Open questions at the time
    • Did not identify the inversin domain mediating tubulin binding
    • Functional consequence of spindle localization not tested
  3. 2004 Medium

    Defined transcript diversity that can selectively delete functional motifs, raising the possibility of isoform-specific inversin activities.

    Evidence Northern blot, RT-PCR, and sequence analysis of INVS splice variants

    PMID:15533716

    Open questions at the time
    • Functional differences between isoforms not characterized
    • Tissue distribution of each isoform not resolved
  4. 2005 Medium

    Mapped inversin expression across renal and many extrarenal tissues, predicting a broad physiological footprint beyond the kidney.

    Evidence Confocal immunostaining of murine tissue sections

    PMID:16007506

    Open questions at the time
    • Did not test function in any extrarenal tissue
    • Subcellular localization within each tissue not resolved
  5. 2010 Low

    Linked C-terminal inversin loss to dysregulated canonical Wnt readouts in patient kidney, hinting at a Wnt-modulating role.

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

    PMID:20798123

    Open questions at the time
    • Single-method protein expression analysis with no mechanistic manipulation
    • Cannot distinguish direct effect from secondary cystic remodeling
  6. 2011 Medium

    Separated the cystic and fibrotic components of inversin loss into distinct kinase pathways, showing the renal phenotype is not a single downstream cascade.

    Evidence Pharmacological p38 and MEK/ERK inhibition in inv/inv mice with western blot, histology, qPCR

    PMID:22076433

    Open questions at the time
    • How inversin loss activates p38 and ERK is unknown
    • Cell type driving each signaling arm not defined
  7. 2012 High

    Positioned inversin within the ciliary gene network by genetic epistasis, defining its compartment and its relationships to NPHP/MKS transition-zone pathways.

    Evidence Live imaging and double-mutant epistasis with nphp/mks genes in C. elegans; mRNA-rescue epistasis placing NEK8 downstream of inv in zebrafish

    PMID:22393243 PMID:22687244

    Open questions at the time
    • Biochemical basis of the directional inv→NEK8 relationship not resolved
    • Inversin's effect on transition-zone protein function vs localization not separated
  8. 2013 High

    Defined the inversin module's composition and an oxygen-sensing input, and identified a direct enzymatic target through which inversin controls cilia stability.

    Evidence Interaction mapping/Co-IP with HIF1AN hydroxylation analysis (zebrafish/Xenopus); in vitro Aurora A kinase assay, Co-IP, MDCK siRNA knockdown with pharmacological rescue

    PMID:23793029 PMID:24026243

    Open questions at the time
    • Functional consequence of INVS hydroxylation on module activity not fully defined
    • How Aurora A inhibition is spatially restricted to the cilium not established
  9. 2014 Medium

    Pinpointed the EF-hand and IQ domains as determinants of ciliary targeting and linked an IQ-domain truncation to human disease via loss of axonemal localization.

    Evidence Domain deletion/mutation with live imaging in C. elegans; immunofluorescence in patient-derived fibroblasts with exome sequencing

    PMID:24677454 PMID:25501555

    Open questions at the time
    • Targeting receptor recognizing the EF-hand not identified
    • Whether calcium binding modulates targeting not tested
  10. 2015 Medium

    Connected the Inversin compartment to a defined ultrastructural region and showed inversin is required for normal motile-cilia architecture and beating, extending its role beyond signaling cilia.

    Evidence Electron microscopy, immunofluorescence, and ciliary beat frequency measurement in inv mutant mice

    PMID:26615802

    Open questions at the time
    • Mechanism linking inversin loss to rootlet malformation unknown
    • Whether motile-cilia defects contribute to organismal phenotype not addressed
  11. 2023 High

    Established that inversin acts cell-autonomously in renal epithelium through cilia-dependent mechanisms and operates in planar cell polarity with NPHP1 and Vangl2, integrating its scaffold, signaling, and disease roles.

    Evidence Cell-type-specific conditional knockouts with genetic cilia removal and VPA treatment in mice; zebrafish invs mutant epistasis with nphp1 and vangl2 with live imaging and apoptosis assays

    PMID:36920028 PMID:37352572

    Open questions at the time
    • Nature of the epithelial-stromal crosstalk driving fibrosis not defined
    • Molecular link between inversin and PCP-associated apoptosis unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the molecular activities of inversin — tubulin scaffolding, Aurora A inhibition, hydroxylation-tuned module assembly, and PCP signaling — are integrated into a single mechanism that prevents renal cyst formation remains unresolved.
  • No unified model linking the ciliary module to downstream p38/ERK and Wnt/PCP outputs
  • Direct catalytic or structural activity of inversin itself unproven
  • Isoform-specific contributions to function untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 1
Partners
ANKS6AURKAHIF1ANNEK8NPHP1NPHP3TUBBVANGL2
Complex memberships
ANKS6-INVS-NPHP3-NEK8 proximal cilium module

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Inversin (INVS/NPHP2) physically interacts with nephrocystin (NPHP1 product), and both proteins colocalize with beta-tubulin to primary cilia of renal tubular cells; knockdown of invs in zebrafish produces PKD-like renal cysts and randomizes heart looping. Co-immunoprecipitation (molecular interaction), immunofluorescence colocalization, 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 association with tubulin is dependent on microtubule polymerization (dissociates after colcemid-mediated depolymerization). Co-immunoprecipitation, co-pelleting assay, immunofluorescence microscopy, microtubule depolymerization/stabilization pharmacology Journal of the American Society of Nephrology : JASN Medium 15213257
2004 Alternative splicing of INVS produces multiple transcript isoforms with skipping of exons 5, 11, or 13, causing loss of specific protein motifs including ankyrin repeats, IQ domains, destruction boxes, and nuclear localization signals. Northern blot, RT-PCR, sequence analysis Genomics Medium 15533716
2005 Inversin localizes to distal tubules in the kidney and to multiple extrarenal tissues including hepatic bile ducts, pancreatic cells, intestinal epithelium, bronchiolar epithelium, cerebellar Purkinje cell dendrites, retinal neural cells, and spermatocytes/spermatids. Laser confocal microscopy of paraffin-embedded murine tissue sections with immunostaining Cell and tissue research Medium 16007506
2012 C. elegans NPHP-2 (inversin ortholog) localizes to the middle segment (Inversin compartment) of sensory cilia and genetically interacts with nphp-1, nphp-4, and MKS pathway genes (mks-1, mks-3, mks-6, mksr-1, mksr-2) to control cilia formation and placement; NPHP-2 is not required for localization of NPHP/MKS transition zone proteins or for intraflagellar transport. Fluorescent protein tagging/live imaging, genetic epistasis, double-mutant analysis in C. elegans Journal of cell science High 22393243
2012 NEK8 (NPHP9) acts downstream of Inv/NPHP2 in zebrafish pronephros morphogenesis and left-right axis establishment; nek8 mRNA rescues inv morphant phenotypes, but inv mRNA cannot rescue nek8 morphant phenotypes; simultaneous knockdown of nek8 and inv synergistically worsens defects. Zebrafish morpholino knockdown, mRNA rescue epistasis experiments FEBS letters Medium 22687244
2013 ANKS6 connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3 in a proximal cilium module; the oxygen sensor HIF1AN hydroxylates both ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 complex. Protein interaction mapping, co-immunoprecipitation, knockdown in zebrafish and Xenopus, identification of HIF1AN as hydroxylase Nature genetics High 23793029
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 in MDCK cells reduces cilia number, and Aurora A/HDAC inhibitors rescue this ciliogenesis defect. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown in MDCK cells, pharmacological rescue Nephrology, dialysis, transplantation High 24026243
2014 The EF hand (calcium-binding) domain of NPHP-2 (C. elegans inversin) is required for its targeting to the Inversin compartment of cilia; the InvC (NPHP-2 domain) and doublet region (ARL-13 domain) are distinct ciliary compartments that interact to regulate ciliogenesis via cilia placement, microtubule ultrastructure, and protein localization. Fluorescent protein tagging, domain deletion/mutation analysis, live imaging in C. elegans, genetic epistasis PLoS genetics Medium 25501555
2015 The Inversin compartment length corresponds to the microtubule doublet region of renal primary cilia; in multiciliated tracheal cells of inv mutant mice, Inv protein is retained at the basal body rather than accumulating in the ciliary Inv compartment, and inv mutant respiratory cilia show rootlet malformation, reduced beating frequency, and reduced beating angle. Electron microscopy, immunofluorescence, ciliary beat frequency measurement in inv mutant mouse Cytoskeleton (Hoboken, N.J.) Medium 26615802
2014 A truncating mutation in the IQ1 domain of inversin causes mislocalization of the mutant protein: in control fibroblasts inversin is present in the ciliary axoneme and basal body, whereas mutant inversin is detected only at the basal body and not in the ciliary axoneme. Immunofluorescence localization in patient-derived fibroblasts, exome sequencing American journal of medical genetics. Part A Medium 24677454
2010 INVS mutation deleting the C-terminus of inversin is associated with abnormal expression of β-catenin and Dishevelled-1 in renal tubular cells, supporting up-regulated canonical Wnt pathway activity. Immunohistochemistry/protein expression analysis in patient kidney tissue Nephrology, dialysis, transplantation Low 20798123
2011 In inv/inv (NPHP2) mouse kidneys, p38 MAPK phosphorylation is elevated; pharmacological inhibition of p38 MAPK reduces renal fibrosis and extracellular matrix gene expression without preventing cyst expansion; MEK/ERK inhibition reduces both cyst expansion and fibrosis independently of p38 MAPK, indicating p38 MAPK and ERK pathways independently regulate different aspects of the inv mutant renal phenotype. Pharmacological inhibition (FR167653 p38 inhibitor; MEK inhibitor) in inv/inv mouse model, western blot, histology, qPCR Nephrology, dialysis, transplantation Medium 22076433
2023 Epithelial-specific knockout of Invs in mice causes renal cyst formation and severe stromal fibrosis, while stromal-specific Invs deletion produces no observable phenotype, establishing an epithelial-cell-autonomous role for Invs and a role for epithelial-stromal crosstalk; concomitant genetic removal of cilia partially suppresses the Invs mutant kidney phenotype, indicating that cilia mediate at least part of Invs function in vivo; valproic acid (HDAC inhibitor) reduces cyst burden and cell proliferation. Cell-type-specific conditional knockout (Cre-lox), genetic cilia removal, pharmacological treatment (VPA), histology, kidney function assays eLife High 36920028
2023 NPHP2/Inversin cooperates with Vangl2 and NPHP1 in planar cell polarity (PCP) signaling during zebrafish cloaca formation; simultaneous depletion of nphp1 and vangl2 in invssa36157 mutants markedly increases cloaca malformations associated with reduced apoptotic activity, while pronephric cell migration and cellular fate are unaffected. Zebrafish mutant line (invssa36157 stop codon), morpholino knockdown, time-lapse imaging, in situ hybridization, apoptosis assays Biochemical and biophysical research communications Medium 37352572

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 497 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 89 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 54 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 29 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 28 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 27 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
2023 Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse. eLife 8 36920028
2015 Structural basis of the Inv compartment and ciliary abnormalities in Inv/nphp2 mutant mice. Cytoskeleton (Hoboken, N.J.) 8 26615802
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 4 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

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