Affinage

INF2

Inverted formin-2 · UniProt Q27J81

Length
1249 aa
Mass
135.6 kDa
Annotated
2026-04-28
83 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INF2 is a multifunctional formin that uniquely combines actin nucleation/elongation with filament severing and depolymerization activities, enabling rapid actin turnover at endoplasmic reticulum–organelle contact sites and controlling organelle dynamics, vesicular trafficking, and microtubule stability. The ER-anchored CAAX isoform drives actin polymerization at ER–mitochondria contacts to promote Drp1-dependent mitochondrial fission, while the non-CAAX isoform maintains Golgi integrity; INF2 is activated by Ca²⁺/calmodulin binding to its N-terminal helix and kept autoinhibited by actin monomer buffering (profilin/thymosin) and a CAP/lysine-acetylated-actin complex engaging the DID (PMID:23349293, PMID:36306014, PMID:41498749, PMID:30962575). INF2 also stabilizes detyrosinated microtubules downstream of mDia1 via IQGAP1 scaffolding, sequesters DYNLL1 to protect nephrin from degradation, and negatively regulates mDia/Rho-mediated SRF transcription through direct DID–DAD cross-interactions with diaphanous formins (PMID:27030671, PMID:33443052, PMID:21278336). Autosomal dominant mutations in the INF2 DID cause focal segmental glomerulosclerosis (FSGS), alone or with Charcot-Marie-Tooth neuropathy, through a gain-of-function mechanism in which constitutive INF2 activation leads to uncontrolled actin polymerization, MRTF-SRF transcriptional reprogramming, nephrin mistrafficking, and dysregulated organelle dynamics (PMID:20023659, PMID:39536114, PMID:38916773).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2009 High

    Establishing that INF2 is an ER-anchored formin regulated by intramolecular DID–DAD autoinhibition resolved how its unique severing and nucleation activities are compartmentalized and restrained at the ER membrane.

    Evidence GFP-fusion imaging, membrane fractionation, farnesylation inhibitor treatment, and in vitro Kd measurement of DID–DAD interaction in mammalian cells

    PMID:19366733

    Open questions at the time
    • How autoinhibition is relieved by upstream signals was unknown
    • Structural basis of ER targeting beyond farnesylation remained unclear
  2. 2009 Medium

    Identification of INF2 DID mutations as causative for autosomal dominant FSGS established the first disease link and implicated disrupted autoinhibition as the disease mechanism.

    Evidence Linkage analysis and sequencing of familial FSGS cohorts

    PMID:20023659

    Open questions at the time
    • Functional proof that DID mutations cause gain-of-function (vs. loss-of-function) was not yet provided
    • Mechanism by which podocytes are specifically vulnerable was unknown
  3. 2010 High

    Discovery that INF2 partners with MAL/MAL2 and Cdc42 to regulate vesicular transcytosis and lumen formation revealed a trafficking function beyond simple actin remodeling.

    Evidence Co-immunoprecipitation, siRNA knockdown, and live videomicroscopy in epithelial cells and T lymphocytes

    PMID:20493814 PMID:20881207

    Open questions at the time
    • Direct structural basis of INF2–MAL interaction was not defined
    • Whether this pathway operates in podocytes or Schwann cells was not tested
  4. 2011 High

    Demonstration that INF2 DID binds and inhibits mDia formins, with FSGS mutations impairing this inhibition, established INF2 as a negative regulator of Rho/mDia signaling and SRF transcription — a trans-regulatory function unprecedented for formins.

    Evidence Yeast two-hybrid, in vitro binding, Co-IP, SRF-luciferase reporter with disease mutants; extended in vivo by zebrafish epistasis showing Dia2/RhoA rescue of INF2 loss

    PMID:21278336 PMID:26086034

    Open questions at the time
    • Whether INF2–mDia interaction occurs under physiological conditions in podocytes remained unresolved
    • Relative contribution of mDia inhibition vs. direct actin remodeling to FSGS pathogenesis was unclear
  5. 2011 High

    Identification of two splice isoforms (CAAX and non-CAAX) with distinct localizations (ER vs. cytosol/Golgi) and the finding that INF2 binds microtubules with high affinity broadened INF2's functional repertoire to include Golgi maintenance and microtubule regulation.

    Evidence siRNA isoform-specific knockdown, digitonin fractionation, latrunculin rescue of Golgi; in vitro MT cosedimentation and TIRF microscopy

    PMID:21998196 PMID:21998204

    Open questions at the time
    • How INF2 chooses between actin and MT substrates in vivo was not determined
    • Physiological signals regulating the non-CAAX isoform were unknown
  6. 2013 High

    The landmark finding that ER-localized INF2 drives actin polymerization at ER–mitochondria contacts to promote Drp1-dependent mitochondrial fission established the INF2–Drp1 axis as a core organelle fission mechanism.

    Evidence siRNA knockdown, live-cell and electron microscopy of ER–mitochondria constriction sites, epistasis with Drp1

    PMID:23349293

    Open questions at the time
    • How INF2 activation is spatially restricted to contact sites was unknown
    • Whether INF2 acts at fission sites of other organelles was untested
  7. 2014 High

    Structural and single-molecule analyses revealed that INF2 severs filaments by FH2 encirclement, with the WH2/DAD amplifying severing 40-fold, providing a mechanistic basis for INF2's unique dual polymerization/severing activity.

    Evidence Two-color TIRF, pyrene-actin assays, 20 Å EM helical reconstruction, domain mutagenesis

    PMID:24412206

    Open questions at the time
    • High-resolution structure of FH2 encircling the filament was not achieved
    • How severing vs. elongation is regulated in the cell remained unclear
  8. 2016 High

    Placement of INF2 downstream of mDia1 in an IQGAP1-scaffolded cascade for detyrosinated microtubule stabilization integrated INF2 into the LPA/Rho signaling axis and explained its role in centrosome reorientation at the immunological synapse.

    Evidence siRNA epistasis, direct IQGAP1–INF2 binding assay, LPA stimulation, formin interaction mutants in fibroblasts and T cells

    PMID:22986496 PMID:27030671

    Open questions at the time
    • How INF2 biochemically promotes microtubule detyrosination was not elucidated
    • Whether IQGAP1 scaffolding operates in podocytes was untested
  9. 2017 High

    Discovery that SPOP-mediated atypical polyubiquitination displaces INF2 from the ER without degradation revealed a non-degradative ubiquitin-based regulatory mechanism controlling mitochondrial fission, with relevance to cancer-associated SPOP mutations.

    Evidence Co-IP, ubiquitination assay, subcellular fractionation, DRP1 puncta quantification with SPOP cancer mutants

    PMID:28448495

    Open questions at the time
    • The ubiquitin chain type and specific lysine sites on INF2 were not identified
    • Whether SPOP regulation occurs in podocytes or neurons was unknown
  10. 2019 High

    Identification of CAP/lysine-acetylated-actin as a 'facilitated autoinhibition' complex that locks INF2 via its DID — with disease mutations disrupting this — provided the first physiological inhibitor and unified the gain-of-function disease mechanism.

    Evidence Purification of inhibitory complex from brain, in vitro reconstitution with acetylmimetic actins, HDAC6 pharmacology, disease mutant testing

    PMID:30962575 PMID:31871199

    Open questions at the time
    • Structural basis of the CAP–KAc-actin–DID ternary complex was not resolved
    • Relative contribution of CAP inhibition vs. DID–DAD autoinhibition in vivo was debated
  11. 2020 High

    Multiple advances solidified the gain-of-function disease model: INF2 R218Q knockin mice showed impaired podocyte recovery, FSGS mutations constitutively activated the calcium-mediated actin response (CaAR), and pathogenic INF2 disrupted DYNLL1 sequestration causing nephrin mistrafficking to lysosomes.

    Evidence R218Q knockin mouse with injury model, CaAR quantification across >50 mutants in patient cells and Drosophila, yeast two-hybrid and nephrin trafficking assays

    PMID:27350175 PMID:32444357 PMID:33443052

    Open questions at the time
    • Whether CMT phenotype involves the same DYNLL1/nephrin pathway was unknown
    • Cell-type-specific activation thresholds explaining FSGS-only vs. CMT+FSGS genotype–phenotype correlation were not mechanistically resolved
  12. 2022 High

    Identification of the N-terminal calmodulin-binding site and demonstration that Ca²⁺/CaM is the physiological activator of INF2 resolved the long-standing question of how INF2 autoinhibition is relieved, and connected INF2 to calcium signaling in neurons (ischemia-protective actinification) and beyond.

    Evidence NMR of N-terminal helices, CaMBS mutagenesis with KO rescue, Ca²⁺-stimulated actin rim assays; NMDA/ischemia models with INF2 silencing/overexpression

    PMID:36229429 PMID:36306014

    Open questions at the time
    • Whether CaM releases the CAP/KAc-actin complex or acts independently was not determined
    • Structural details of full-length INF2 conformational change upon CaM binding were lacking
  13. 2024 High

    Definitive proof that FSGS-causing INF2 mutations act via gain-of-function came from comparison of knockin vs. knockout mice: only R218Q knockin (not KO) developed glomerular disease, and pathogenic INF2 drove MRTF-SRF nuclear translocation, transcriptome reprogramming, and mitotic catastrophe.

    Evidence KI vs. KO mouse with puromycin injury, RNA-seq of R218Q glomeruli, MRTF imaging, human kidney organoids; catalytic-dead mutant rescue

    PMID:38916773 PMID:39536114

    Open questions at the time
    • Whether MRTF-SRF inhibition is a viable therapeutic strategy in vivo was not tested
    • Contribution of mitotic abnormalities to slowly progressive podocyte loss in human disease was not established
  14. 2024 High

    Extension of the DYNLL1 mechanism showed that released DYNLL1 binds PI31 to redirect nephrin to proteasomal degradation, and proteasome inhibition rescued nephrin levels in vivo, providing a potential therapeutic angle for INF2-FSGS.

    Evidence Co-IP of DYNLL1–PI31, bortezomib treatment in R218Q KI mouse puromycin model, nephrin trafficking assays

    PMID:39621430

    Open questions at the time
    • Long-term efficacy and safety of proteasome inhibition for FSGS is unknown
    • Whether other slit diaphragm proteins are similarly affected was not tested
  15. 2025 High

    A reconstituted cell-free system revised the autoinhibition model: CAP proteins are dispensable for INF2 autoinhibition, which instead requires actin monomer buffering by profilin or thymosin β4, and the N-terminus has regulatory functions beyond CaM binding.

    Evidence Cell-free INF2 regulation assay with profilin/thymosin titration, CaM binding, N-terminal mutants

    PMID:41498749

    Open questions at the time
    • The precise role of the N-terminal region beyond CaM binding is not yet defined
    • How profilin-mediated autoinhibition integrates with CAP/KAc-actin inhibition in cells is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length INF2 in autoinhibited and active states, the spatial mechanisms governing INF2 activation selectively at ER–organelle contact sites, and whether therapeutic targeting of the gain-of-function mechanism can prevent or reverse FSGS/CMT remain major open questions.
  • No high-resolution structure of full-length INF2 or INF2–actin filament complex exists
  • Mechanism of spatial restriction of INF2 activation to specific ER subdomains is unknown
  • No therapeutic strategy targeting INF2 gain-of-function has been validated in clinical settings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 6 GO:0098772 molecular function regulator activity 5
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-5653656 Vesicle-mediated transport 4
Partners
CALM1CDC42DIAPH1DYNLL1IQGAP1MALMAL2SPOP

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 INF2 is peripherally bound to the cytoplasmic face of the endoplasmic reticulum (ER) via a C-terminal farnesyl (CAAX) modification; farnesylation is required but not sufficient for ER association, with ionic interactions also important. The WH2 motif functions as a DAD that binds the DID with Kd ~1.1 µM, and this DID-DAD interaction inhibits INF2's depolymerization activity but not its nucleation activity. DAD/WH2 mutations that abolish DID-DAD binding cause ER collapse around the nucleus with actin accumulation. GFP-fusion live-cell imaging, membrane fractionation/extraction, farnesylation inhibitor treatment, in vitro binding assay (apparent Kd measurement), site-directed mutagenesis Journal of cell science High 19366733
2009 Mutations in the diaphanous inhibitory domain (DID) of INF2 cause autosomal dominant FSGS; all disease-causing mutations reside in the DID, a region that interacts with the DAD and competes for actin monomer binding, implicating disrupted autoinhibitory DID-DAD interaction in disease. Linkage analysis, sequencing of familial FSGS cohort, conservation analysis of mutated residues Nature genetics Medium 20023659
2010 INF2 interacts with MAL2 and regulates basolateral-to-apical transcytosis and lumen formation in epithelial cells. Both actin polymerization and depolymerization activities of INF2 are required. INF2 binds Cdc42 in a GTP-loaded-dependent manner, and Cdc42 and INF2 together regulate MAL2 vesicle dynamics and transcytosis. Co-immunoprecipitation, knockdown (siRNA), live videomicroscopy, organotypic culture lumen formation assay, GTPase binding assay Developmental cell High 20493814
2010 INF2 interacts with MAL in T lymphocytes and colocalizes at the cell periphery, pericentriolar endosomes, and along microtubules. Knockdown of INF2 reduces MAL+ transport vesicle formation and Lck levels at the plasma membrane, impairing immunological synapse formation. Both actin polymerization and depolymerization activities of INF2 are required for efficient Lck targeting. Cdc42 and Rac1, which bind INF2, regulate this transport. Co-immunoprecipitation, siRNA knockdown, videomicroscopy, flow cytometry (surface Lck), immunological synapse assay Blood High 20881207
2011 INF2 DID binds directly to the DADs of mDia1, mDia2, and mDia3 (diaphanous-related formins); this interaction inhibits mDia-mediated Rho-activated actin polymerization and SRF-responsive transcription. Disease-causing INF2 DID mutations (E184K, R218Q) show decreased capacity to inhibit SRF activation and gene transcription, suggesting that DID mutations impair inhibition of mDia signaling. Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, colocalization (immunofluorescence), SRF-luciferase reporter assay Proceedings of the National Academy of Sciences of the United States of America High 21278336
2011 INF2 exists as two C-terminal splice variants: CAAX (ER-localized via farnesyl group, actin-independent) and non-CAAX (localizes to an actin-dependent meshwork). Suppression of INF2-non-CAAX causes Golgi apparatus fragmentation, an effect reversed by latrunculin B treatment. Discrete actin patches in the peri-Golgi region are reduced upon INF2 suppression. siRNA knockdown, digitonin extraction (fractionation), latrunculin B treatment, fluorescence microscopy Molecular biology of the cell High 21998196
2011 INF2 (FH1-FH2-C construct) binds microtubules with high affinity (Kd < 100 nM) and bundles microtubules, reducing catastrophe rate. Microtubule bundling requires the C-terminus of INF2. Actin monomers inhibit microtubule binding/bundling by INF2 but microtubules do not inhibit INF2-mediated actin polymerization, distinguishing INF2 from mDia1/mDia2. In vitro microtubule co-sedimentation, TIRF microscopy, biochemical binding assays Molecular biology of the cell High 21998204
2011 INF2 mutations causing CMT with FSGS perturb the INF2-MAL-CDC42 pathway, resulting in actin cytoskeleton disorganization, enhanced INF2 binding to CDC42, and mislocalization of INF2, MAL, and CDC42 in Schwann cells. INF2 colocalizes and interacts with MAL in Schwann cells. Co-immunoprecipitation, immunohistochemistry, cell culture functional studies with patient-derived mutations The New England journal of medicine High 22187985
2012 INF2 FH2 domain mutations I643A and K792A have unexpected effects: I643A causes tight capping of a subset of filaments and nearly abolishes severing/depolymerization without abolishing barbed-end binding; K792A causes slow elongation with minor effects on severing. In cells, I643A cannot promote actin polymerization because it is unable to elongate in the presence of capping protein. Pyrene-actin assembly assay, TIRF microscopy, site-directed mutagenesis, cell expression assay The Journal of biological chemistry High 22879592
2012 INF2 is required for formation of detyrosinated (stable) microtubules after T cell receptor engagement, and this is essential for centrosome reorientation to the immunological synapse. The FH2 domain of INF2 mediates centrosome repositioning and can rescue DIA1-, FMNL1-, Rac1-, and Cdc42-deficient cells, placing INF2 downstream of or parallel to these factors. siRNA knockdown, genetic epistasis rescue experiments, immunofluorescence for detyrosinated tubulin, centrosome polarization assay The Journal of cell biology High 22986496
2013 ER-localized INF2 mediates actin polymerization at ER-mitochondria contact sites to drive mitochondrial constriction and fission, functioning upstream of Drp1. Actin filaments accumulate between mitochondria and INF2-enriched ER at constriction sites. INF2 knockdown reduces mitochondrial fission. siRNA knockdown, live-cell imaging, electron microscopy, dominant-negative INF2 expression, epistasis with Drp1 Science (New York, N.Y.) High 23349293
2014 INF2 severs actin filaments through FH2 domain encirclement of the filament; a single INF2 dimer can sever filaments in a phosphate-release-dependent manner. The C-terminal DAD/WH2 motif increases severing potency 40-fold by binding adjacent actin protomers to further disrupt filament structure. Helical 3D reconstruction at 20 Å resolution shows FH2 encircling the filament. Two-color TIRF microscopy, pyrene-actin assay, ADP/ADP-Pi filament binding assay, electron microscopy (helical reconstruction), domain truncation/mutagenesis Current biology : CB High 24412206
2014 INF2 knockdown in zebrafish causes edema, podocyte dysfunction, and altered glomerular filtration barrier associated with mistrafficking of slit diaphragm proteins (nephrin/podocin) and disinhibited mDia (Dia2) activity. This phenotype is rescued by wild-type INF2 but not disease-causing INF2 mutants, and also rescued by loss of RhoA or Dia2, genetically placing INF2 as a negative regulator of Rho/Dia signaling in podocytes. Morpholino knockdown in zebrafish, rescue with wild-type vs. mutant INF2, double knockdown epistasis (RhoA, Dia2), immunofluorescence of slit diaphragm proteins EBioMedicine High 26086034
2015 INF2 generates short actin filaments (<60 nm) that continuously turn over through a cycle of barbed-end elongation, severing, and WH2-mediated depolymerization. The rate-limiting step is nucleotide exchange on actin monomers after release from INF2. Profilin accelerates turnover 6-fold and shifts the equilibrium toward polymerization. Pyrene-actin assay, TIRF microscopy, biochemical kinetics with domain truncations and profilin addition The Journal of biological chemistry High 26124273
2015 C. elegans EXC-6 (INF2 ortholog) regulates F-actin and microtubule cytoskeleton at excretory cell tips during tubulogenesis; disease-associated INF2 mutations cause constitutive activity in this system. Activated INF2 can substitute for EXC-6, and genetic analysis places EXC-6 function in organizing both F-actin and MT arrays for basolateral outgrowth and lumen formation. C. elegans genetics, live imaging, rescue with activated/mutant human INF2, genetic epistasis Developmental cell High 25771894
2016 INF2 acts downstream of mDia1 in a formin activation cascade to stabilize detyrosinated microtubules (Glu MTs) in fibroblasts after LPA stimulation. IQGAP1 scaffolds this cascade by directly binding the C-terminus of INF2 and facilitating LPA-induced mDia1-INF2 interaction and INF2 localization to MTs. Mutants disrupting mDia1-INF2 interaction fail to rescue MT stability in cells depleted of the respective formin. siRNA knockdown epistasis, direct N-IQGAP1/C-INF2 binding assay (pulldown), LPA-induced colocalization, formin interaction mutants Molecular biology of the cell High 27030671
2016 Mice with the FSGS-associated INF2 R218Q knockin mutation show impaired reversal of protamine sulfate-induced podocyte foot process effacement; mutant podocytes display persistent cytoplasmic nephrin/podocin aggregation, nephrin phosphorylation, and impaired recovery of mDia membrane localization, demonstrating that normal INF2 is required for actin-based recovery from podocyte injury. Knockin mouse model, protamine sulfate/heparin perfusion model, immunofluorescence of slit diaphragm proteins, podocyte primary culture Kidney international High 27350175
2017 SPOP (CUL3-RBX1 E3 ubiquitin ligase adaptor) recognizes a Ser/Thr-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2 that reduces INF2 ER localization and mitochondrially associated DRP1 puncta formation without causing INF2 degradation, thereby inhibiting mitochondrial fission. Cancer-associated SPOP mutants increase INF2 ER localization and promote fission through dominant-negative inhibition of endogenous SPOP. Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, DRP1 puncta quantification, SPOP mutant expression PLoS genetics High 28448495
2019 INF2 is inhibited by a complex of lysine-acetylated actin (KAc-actin) bound to cyclase-associated protein (CAP), purified from mouse brain tissue. This inhibition requires the INF2 DID. Treatment with HDAC6 releases INF2 inhibition, and HDAC6 inhibitors block cellular INF2 activation. Disease-associated INF2 DID mutants are poorly inhibited by CAP-KAc-actin, suggesting FSGS/CMT mutations reduce CAP-KAc-actin binding. Biochemical purification of inhibitory complex from brain tissue, in vitro actin polymerization assay, HDAC6 treatment, HDAC6 inhibitor (tubastatin A) in cells, mutagenesis Nature cell biology High 30962575
2019 Lysine residues K50 and K61 on actin are the key sites for CAP/KAc-actin-mediated INF2 inhibition. K50Q- and K61Q-actin (acetylmimetic) bound to CAP2 inhibit full-length INF2 in a DID-dependent manner. The CAP WH2 domain binds INF2-DID with submicromolar affinity; INF2-DAD binds CAP/K50Q-actin 5-fold better than CAP/WT-actin, supporting a bridging model between INF2 DID and DAD. Lysine-to-glutamine acetylmimetic mutations, in vitro INF2 inhibition assay, direct binding studies, U2OS cell overexpression Proceedings of the National Academy of Sciences of the United States of America High 31871199
2020 INF2-CAAX isoform is the predominant isoform in podocytes. INF2 is proteolytically cleaved by cathepsin proteases, liberating the N-terminal DID fragment. The N-terminal fragment localizes to podocyte foot processes (but not with FSGS mutations), binds mDIA1, and promotes cell spreading in a cleavage-dependent manner. FSGS-associated R218Q mutation impairs N-fragment localization and function but not cleavage itself. Western blot (isoform/cleavage analysis), cathepsin inhibitors, co-immunoprecipitation (N-fragment/mDIA1), podocyte spreading assay, immunofluorescence Journal of the American Society of Nephrology : JASN High 31924668
2020 INF2 mutations cause constitutive activation of formin activity and a deregulated calcium-mediated actin reset (CaAR) stress response. FSGS-only mutations are distinguishable from CMT+FSGS mutations by degree of INF2 activation, enabling genotype-phenotype correlation. This was validated in primary patient cells and Drosophila nephrocytes. Quantitative live-cell imaging of CaAR, primary patient cells, Drosophila nephrocyte functional assay, panel of >50 disease mutants Journal of the American Society of Nephrology : JASN High 32444357
2020 INF2 interacts with dynein light chain 1 (DYNLL1), and pathogenic INF2 mutations (R218Q) disrupt this interaction, diverting dynein-mediated post-endocytic sorting of nephrin from recycling endosomes to lysosomes for degradation. Antagonizing dynein-mediated transport rescues this defect. Yeast two-hybrid screen, live cell imaging, fluorescent/surface biotinylation trafficking assays, INF2 transgenic mouse model, dynein antagonism Journal of the American Society of Nephrology : JASN High 33443052
2022 The N-terminal extension of INF2 forms two α-helices; the first helix contains the sole calmodulin (CaM)-binding site (CaMBS) with key residues W11, L14, L18 (1-4-8 motif). CaM C-terminal lobe directly interacts with this helix. Ca2+/CaM binding activates INF2: INF2 KO cells do not form the perinuclear F-actin ring or respond to Ca2+ elevation with actin polymerization; expression of INF2 with inactivated CaMBS fails to rescue these defects. NMR spectroscopy, biochemical binding assays, INF2 KO cell complementation, Ca2+ stimulation assay, CaMBS mutagenesis (W11, L14, L18) Cellular and molecular life sciences : CMLS High 36306014
2022 Ischemia and excess NMDA receptor activation cause INF2-dependent actin reorganization (actinification) within the somatodendritic compartment: F-actin depolymerizes from spines and polymerizes into stable filaments in dendritic shafts/soma. Ca2+ influx combined with spine F-actin depolymerization activates INF2. INF2 silencing renders neurons vulnerable to ischemic death; INF2 overexpression is protective. siRNA knockdown, INF2 overexpression, live-cell F-actin imaging, NMDA application, photothrombotic stroke model in mouse, ion flux measurements Nature communications High 36229429
2022 INF2 forms an 8S complex with actin (4 actin monomers:2 INF2 dimers) in which actin monomers are arranged in parallel orientation. The 8S particles can seed actin assembly. INF2 accelerates the disassembly of oxidized (Mox) F-actin. Negative-stain electron microscopy (2D class averages), chemical crosslinking, pyrene-actin assembly seeding assay Journal of biomolecular structure & dynamics Medium 35343388
2024 AMPK phosphorylates INF2 at Ser1077 under energy stress, increasing INF2 localization to the ER and enhancing DRP1 recruitment to mitochondria, thereby promoting mitochondrial fission and endometrial cancer cell growth. In vitro kinase assay, phospho-specific immunoblot, ER localization imaging, DRP1 co-localization, siRNA knockdown, immunohistochemistry Cell death & disease Medium 38233384
2024 FBXO7 E3 ubiquitin ligase ubiquitinates INF2 and targets it for degradation, thereby inhibiting INF2-DRP1 axis-mediated mitochondrial fission. ECa-associated FBXO7 mutants are defective in INF2 ubiquitination and degradation, promoting mitochondrial hyper-fission. Co-immunoprecipitation, ubiquitination assay, protein stability assay (cycloheximide chase), siRNA knockdown, DRP1 inhibitor (Mdivi-1) Cell death & disease Medium 37344480
2024 INF2 R218Q knockin mice (but not INF2 knockout mice) are susceptible to glomerular disease upon puromycin aminonucleoside challenge, demonstrating a gain-of-function disease mechanism. R218Q INF2 alters actin cytoskeleton content and INF2 localization. Adhesion and mitochondria-related pathways are enriched in R218Q glomeruli. Patient-derived organoid podocytes with S186P INF2 recapitulate adhesion and mitochondrial phenotypes. Knockin vs. knockout mouse comparison, puromycin aminonucleoside injury model, colocalization, co-immunoprecipitation, actin measurements, RNA-seq, human kidney organoids Science advances High 39536114
2024 INF2 R218Q mutation disrupts sequestration of DYNLL1 by INF2, allowing DYNLL1-PI31 interaction that promotes dynein-mediated transport of nephrin to the proteasome for degradation. Proteasome inhibition with bortezomib stabilizes nephrin in R218Q podocytes and ameliorates FSGS in vivo. Co-immunoprecipitation (DYNLL1-PI31), siRNA knockdown of DYNLL1/PI31, proteasome inhibitor treatment, nephrin trafficking assay, R218Q KI mouse puromycin model Kidney360 High 39621430
2024 Pathogenic INF2 variants cause ER dysmorphism (shift from tubular to sheet-like ER), mitochondrial fragmentation with peripheral misdistribution, and impaired lysosomal trafficking; CMT+FSGS variants cause more severe ER and mitochondrial disruption than FSGS-only variants, linked to greater cytoskeletal disorganization. High-resolution live imaging of HeLa cells expressing INF2 variants, ER/mitochondria morphology quantification, actin and MT inhibitor treatments International journal of molecular sciences Medium 39337270
2024 Pathogenic INF2 promotes translocation of transcriptional cofactor MRTF to the nucleus, causing sustained MRTF-SRF transcriptional complex activation, profound transcriptome reprogramming, multipolar spindle assembly, multi-micronucleation, and cell death. Reducing MRTF-SRF activation mitigates nuclear abnormalities. Inactivation of the INF2 catalytic domain prevents aberrant nuclei. RNA sequencing, MRTF localization imaging, retroviral/plasmid expression of pathogenic INF2 in renal epithelial and primary podocyte cells, catalytic domain inactivation Cellular and molecular life sciences : CMLS Medium 38916773
2024 INF2-mediated actin polymerization at ER-organelle contact sites regulates the size and movement of mitochondria, endosomes, and lysosomes; ER-associated actin consistently marks fission sites for all three organelle types. Live imaging of organelle dynamics, ER-associated actin visualization, INF2 knockdown/overexpression, organelle fission site analysis Research square (preprint)preprint Medium 39184068
2024 CAP1 and CAP2 (cyclase-associated proteins) inhibit INF2 in neurons to permit dendritic spine maturation. Overactivation of INF2 impairs spine maturation, and INF2 inactivation rescues spine defects in CAP-deficient hippocampal neurons, placing CAP-mediated INF2 inhibition as a molecular switch for filopodia-to-mature-spine transition. Genetic inactivation (KO) of CAP1/CAP2, INF2 overactivation/inactivation in hippocampal neurons, spine density/morphology imaging Cellular and molecular life sciences : CMLS Medium 39154297
2025 Piezo1/Ca2+ signaling activates INF2 to induce widespread actin cytoskeletal remodeling, promoting de-adhesion and mesenchymal-to-amoeboid transition (MAT) in melanoma cells in confined environments. INF2 activation is required for cells to effectively migrate in mechanically challenging environments. Piezo1 inhibition/activation, Ca2+ imaging, INF2 KD, confinement microchannels, amoeboid migration quantification, de-adhesion assay Current biology : CB Medium 40120583
2026 INF2 autoinhibition does not require CAP proteins but does require actin monomer 'buffering' by profilin or thymosin; Ca2+-bound calmodulin (CALM) activates INF2 through binding to the N-terminus; the N-terminus has additional regulatory roles beyond CALM binding. This was established with a novel cell-free INF2 regulation assay. Cell-free in vitro assay for INF2 regulation, calmodulin binding assay, profilin/thymosin titration, N-terminus mutants The Journal of cell biology High 41498749
2020 INF2 negatively regulates CFTR levels at the plasma membrane: reduction of INF2 levels promotes CFTR trafficking to the PM under EPAC1 activation, identified by protein interaction profiling and validated by knockdown. Protein interaction profiling (proteomics), siRNA knockdown, surface CFTR measurement The Biochemical journal Low 32573649
2021 EV71 infection causes INF2 cleavage at Asp1051, mediated predominantly by activated caspase-2. Subcellular localization of INF2 and caspase-2 is altered in infected cells, suggesting caspase-2-mediated INF2 cleavage is involved in viral replication organelle formation. Caspase inhibitor treatment, site-directed mutagenesis of cleavage site, subcellular fractionation/immunofluorescence Frontiers in microbiology Low 34046026
2023 Drebrin protects assembled actin filaments from INF2-mediated severing without inhibiting INF2's polymerization activity; truncated drebrin (DrbA1-300) is sufficient for this protection. This competitive regulation of actin dynamics is relevant to specialized cells such as neurons and podocytes. In vitro severing/polymerization assays, electron microscopy, TIRF microscopy, domain truncation Journal of molecular biology Medium 38158176
2025 The WH2/DAD of INF2 forms a single α-helix (by NMR); the hydrophobic N-terminal region of the WH2/DAD is essential for INF2-mediated actin polymerization and for inducing nuclear abnormalities. Deletion of the entire WH2/DAD or its hydrophobic region abolishes INF2 activity. The WH2/DAD undergoes a conformational change to facilitate actin binding. NMR spectroscopy, deletion/point mutants of WH2/DAD, cell expression of INF2 variants with F-actin and nuclear phenotype quantification The FEBS journal High 40993919
2025 ERM proteins (Ezrin, Radixin, Moesin) localize to the nuclear envelope and contribute to perinuclear actin rim formation downstream of INF2/Ca2+ activation; ERM overexpression increases perinuclear actin rim levels while ERM knockdown reduces them. Emerin (a nuclear membrane actin-binding protein) is not required for the perinuclear actin rim. ERM knockdown/overexpression, emerin KO, Ca2+-induced actin rim imaging in melanoma cells bioRxiv (preprint)preprint Low bio_10.1101_2025.02.22.639617

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science (New York, N.Y.) 666 23349293
2009 Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nature genetics 356 20023659
2011 INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. The New England journal of medicine 219 22187985
2011 Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. Journal of the American Society of Nephrology : JASN 122 21258034
2011 Differential interactions of the formins INF2, mDia1, and mDia2 with microtubules. Molecular biology of the cell 114 21998204
2009 INF2 is an endoplasmic reticulum-associated formin protein. Journal of cell science 114 19366733
2012 Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney international 100 23014460
2010 The formin INF2 regulates basolateral-to-apical transcytosis and lumen formation in association with Cdc42 and MAL2. Developmental cell 82 20493814
2018 INF2 regulates oxidative stress-induced apoptosis in epidermal HaCaT cells by modulating the HIF1 signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 78 30579254
2011 Splice variant-specific cellular function of the formin INF2 in maintenance of Golgi architecture. Molecular biology of the cell 73 21998196
2012 INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells. The Journal of cell biology 72 22986496
2011 Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). Proceedings of the National Academy of Sciences of the United States of America 72 21278336
2017 Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer. PLoS genetics 64 28448495
2019 A complex containing lysine-acetylated actin inhibits the formin INF2. Nature cell biology 57 30962575
2014 INF2-mediated severing through actin filament encirclement and disruption. Current biology : CB 55 24412206
2010 Formin INF2 regulates MAL-mediated transport of Lck to the plasma membrane of human T lymphocytes. Blood 55 20881207
2016 An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells. Molecular biology of the cell 49 27030671
2012 Mutations to the formin homology 2 domain of INF2 protein have unexpected effects on actin polymerization and severing. The Journal of biological chemistry 45 22879592
2019 Regulation of INF2-mediated actin polymerization through site-specific lysine acetylation of actin itself. Proceedings of the National Academy of Sciences of the United States of America 43 31871199
2016 Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury. Kidney international 42 27350175
2015 The disease-associated formin INF2/EXC-6 organizes lumen and cell outgrowth during tubulogenesis by regulating F-actin and microtubule cytoskeletons. Developmental cell 42 25771894
2018 Tanshinone IIA promotes IL2-mediated SW480 colorectal cancer cell apoptosis by triggering INF2-related mitochondrial fission and activating the Mst1-Hippo pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 30372868
2020 The formin INF2 in disease: progress from 10 years of research. Cellular and molecular life sciences : CMLS 39 32451589
2013 De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy. Neurology 37 24174593
2015 Assembly and turnover of short actin filaments by the formin INF2 and profilin. The Journal of biological chemistry 31 26124273
2020 A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles. Journal of the American Society of Nephrology : JASN 30 32444357
2014 Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy. Journal of neuropathology and experimental neurology 27 24487800
2014 Novel INF2 mutations in an Italian cohort of patients with focal segmental glomerulosclerosis, renal failure and Charcot-Marie-Tooth neuropathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 27 25165188
2022 INF2-mediated actin filament reorganization confers intrinsic resilience to neuronal ischemic injury. Nature communications 25 36229429
2014 Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus. EBioMedicine 24 26086034
2010 Variable renal phenotype in a family with an INF2 mutation. Pediatric nephrology (Berlin, Germany) 24 20803156
2020 FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes. Journal of the American Society of Nephrology : JASN 22 31924668
2012 Novel INF2 mutation p. L77P in a family with glomerulopathy and Charcot-Marie-Tooth neuropathy. Pediatric nephrology (Berlin, Germany) 22 22961558
2020 Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy. Journal of the American Society of Nephrology : JASN 21 33443052
2018 Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities. Breast cancer : basic and clinical research 21 30158824
2020 Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation. The Biochemical journal 19 32573649
2018 Nur77 promotes cerebral ischemia-reperfusion injury via activating INF2-mediated mitochondrial fragmentation. Journal of molecular histology 19 30298449
2019 Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission. Journal of cellular physiology 18 30741413
2018 Nurr1 exacerbates cerebral ischemia-reperfusion injury via modulating YAP-INF2-mitochondrial fission pathways. The international journal of biochemistry & cell biology 17 30267803
2024 Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer. Cell death & disease 16 38233384
2016 Diagnosing FSGS without kidney biopsy - a novel INF2-mutation in a family with ESRD of unknown origin. BMC medical genetics 14 27733133
2014 A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis. Journal of the peripheral nervous system : JPNS 14 24750328
2016 INF2- and FHOD-related formins promote ovulation in the somatic gonad of C. elegans. Cytoskeleton (Hoboken, N.J.) 13 27770600
2015 INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients. Clinical neuropathology 11 25943269
2023 FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division. Cell death & disease 10 37344480
2024 INF2 mutations cause kidney disease through a gain-of-function mechanism. Science advances 9 39536114
2019 A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction. Journal of the peripheral nervous system : JPNS 9 30680856
2024 Altered Endoplasmic Reticulum Integrity and Organelle Interactions in Living Cells Expressing INF2 Variants. International journal of molecular sciences 7 39337270
2017 Mutations in INF2 may be associated with renal histology other than focal segmental glomerulosclerosis. Pediatric nephrology (Berlin, Germany) 7 29038887
2024 Regulation of formin INF2 and its alteration in INF2-linked inherited disorders. Cellular and molecular life sciences : CMLS 6 39586895
2022 Structure and function of the N-terminal extension of the formin INF2. Cellular and molecular life sciences : CMLS 6 36306014
2016 Reduced INF2 expression in nephrotic syndrome is possibly related to clinical severity of steroid resistance in children. Nephrology (Carlton, Vic.) 6 26383224
2024 Cyclase-associated protein (CAP) inhibits inverted formin 2 (INF2) to induce dendritic spine maturation. Cellular and molecular life sciences : CMLS 5 39154297
1996 Photodissimilation of Fructose to H(inf2) and CO(inf2) by a Dinitrogen-Fixing Cyanobacterium, Anabaena variabilis. Applied and environmental microbiology 5 16535288
2025 The activation of INF2 by Piezo1/Ca2+ is required for mesenchymal-to-amoeboid transition in confined environments. Current biology : CB 4 40120583
1996 Biosynthesis of Poly(3-Hydroxyalkanoic Acid) Copolymer from CO(inf2) in Pseudomonas acidophila through Introduction of the DNA Fragment Responsible for Chemolithoautotrophic Growth of Alcaligenes hydrogenophilus. Applied and environmental microbiology 4 16535252
2024 Functional genetic variants of the disulfidptosis-related INF2 gene predict survival of hepatitis B virus-related hepatocellular carcinoma. Carcinogenesis 3 38270181
2024 INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death. Cellular and molecular life sciences : CMLS 3 38916773
2023 Characterization of Expression and Function of the Formins FHOD1, INF2, and DAAM1 in HER2-Positive Breast Cancer. Journal of breast cancer 3 37985384
2022 Parallel actin monomers in the 8S complex of actin-INF2. Journal of biomolecular structure & dynamics 3 35343388
2021 INF2 p.Arg214Cys mutation in a Chinese family with rapidly progressive renal failure and follow-up of renal transplantation: case report and literature review. BMC nephrology 3 33541266
2025 De novo somatic mosaicisms of INF2 and TRPV4 in patients with Charcot-Marie-Tooth disease. Genes & genomics 2 40257654
2024 Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS). bioRxiv : the preprint server for biology 2 38915495
2021 Enterovirus 71 Induces INF2 Cleavage via Activated Caspase-2 in Infected RD Cells. Frontiers in microbiology 2 34046026
2025 Structural and functional dissection of the WH2/DAD motif of INF2, a formin linked to human inherited degenerative disorders. The FEBS journal 1 40993919
2024 The activation of INF2 by Piezo1/Ca2+ is required for mesenchymal to amoeboid transition in confined environments. bioRxiv : the preprint server for biology 1 37745412
2024 INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement. Research square 1 39184068
2024 Dynll1-PI31 Interaction Enhances Proteolysis Through the Proteasome, Representing a Novel Therapeutic Target for INF2-Related FSGS. Kidney360 1 39621430
2023 INF2 and ROBO2 gene mutation in an Indian family with end stage renal failure and follow-up of renal transplantation. Nephrology (Carlton, Vic.) 1 37772439
2023 Drebrin Protects Assembled Actin from INF2-FFC-mediated Severing and Stabilizes Cell Protrusions. Journal of molecular biology 1 38158176
2010 The inverted Formin INF2 sorts it out. Developmental cell 1 20493801
1994 Selection of soybean plant leaves which yield mesophyll cell isolates with maximal rates of CO2 and NO inf2 (sup-) photoassimilation. Photosynthesis research 1 24311219
2026 Regulation of the formin INF2 by actin monomers and calcium/calmodulin. The Journal of cell biology 0 41498749
2026 A very rare case report with INF2 gene mutation related sporadic FSGS and response to treatment. Nefrologia 0 41997690
2025 Nerve Enlargement in Patients with INF2 Variants Causing Peripheral Neuropathy and Focal Segmental Glomerulosclerosis. Biomedicines 0 39857711
2025 Formin INF2 supplementation alleviates cytoskeleton-based mitochondria defects for oocyte quality under obesity. Free radical biology & medicine 0 40180021
2025 Targeting INF2 with DiosMetin 7-O-β-D-Glucuronide: a new stratagem for colorectal cancer therapy. BMC cancer 0 40452021
2025 INF2-Related Charcot-Marie-Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights. Annals of clinical and translational neurology 0 40985697
2025 Generation of a human iPSC line (NUMNi002-A) from a patient with nephrotic syndrome harboring an INF2 gene variant. Stem cell research 0 40992252
2025 Autosomal dominant focal segmental glomerulosclerosis by INF2 p.Arg218Trp and p.Ser186Pro mutations: three case reports and literature review. BMC nephrology 0 41094651
2025 Regulation of the formin INF2 by actin monomers and calcium-calmodulin. bioRxiv : the preprint server for biology 0 41279891
2025 High Diagnostic Yield of Genetic Screening in Autosomal Dominant Steroid-Resistant Nephrotic Syndrome: Predominance of INF2 and TRPC6 and Identification of a Novel Gene. Nephrology (Carlton, Vic.) 0 41326026
2024 Co-occurrence of Charcot-Marie-Tooth disease type 1 and glomerulosclerosis in a patient with a de novo INF2 variant. BMC nephrology 0 39609740