KATNAL2

KATNAL2 is a katanin-family AAA-ATPase that acts on microtubule-based structures to control cytokinesis, ciliogenesis, sperm differentiation, and neuronal morphogenesis (PMID:26153462, PMID:29136647, PMID:38916997). It localizes to interphase microtubules, centrioles, the mitotic spindle, the midbody, and the basal body/axoneme of cilia, and loss of function in cultured cells causes inefficient cytokinesis, supernumerary centrioles, multipolar spindles, multinuclearity, increased microtubule acetylation, and strongly impaired ciliogenesis (PMID:26153462). Domain dissection of the ciliate ortholog defines a tripartite architecture in which an N-terminal LisH domain mediates dimerization, protein stability, and localization to basal bodies and ciliary doublets, with targeting sensitive to microtubule glutamylation, while the C-terminal AAA domain provides catalytic activity (PMID:31991798). In spermatogenesis KATNAL2 initiates sperm tail growth from the basal body, shapes the sperm head through the manchette, and supports acrosome attachment and sperm release, acting either with the regulatory subunit KATNB1 or autonomously, and operating on the noncanonical δ- and ε-tubulin polymers of the manchette together with TUBD1/KATNB1 (PMID:29136647, PMID:40586731). In the nervous system KATNAL2 is required for dendritic arborization, and mouse models link its loss to cerebral ventriculomegaly arising from disrupted ependymal cilia and planar cell polarity with impaired CSF flow, alongside ASD-like synaptic, transcriptomic, and behavioral deficits; an ASD-associated F244L missense variant recapitulates ventriculomegaly, and early postnatal re-expression rescues the ciliary, ventricular, and behavioral phenotypes, establishing a defined developmental window (PMID:27161796, PMID:38916997, PMID:38718086). KATNAL2 physically interacts with the centriolar P-loop NTPases Nubp1 and Nubp2 and sits within the broader katanin interaction network (PMID:26153462, PMID:26929214).

1. 2015 High

   Established KATNAL2 as a microtubule-associated factor whose isoforms decorate centrioles, spindle, midbody, and cilia and are required for faithful cytokinesis and ciliogenesis, defining its core cellular roles.

   Evidence shRNAi knockdown, stable overexpression, and immunofluorescence localization across five isoforms in cultured murine cells

   PMID:26153462

   Open questions at the time

   • Does not demonstrate microtubule-severing biochemical activity directly
   • Does not resolve which isoform drives which phenotype
   • Mechanism linking KATNAL2 to centriole number control unknown
2. 2015 Medium

   Identified centriolar P-loop NTPases Nubp1/Nubp2 as direct KATNAL2 partners, placing it among centriole-resident negative regulators of ciliogenesis.

   Evidence In vivo co-immunoprecipitation and direct interaction assays with multiple isoforms

   PMID:26153462

   Open questions at the time

   • No reconstitution or interaction-mapping mutagenesis
   • Functional consequence of the interaction not tested
   • No reciprocal endogenous validation
3. 2016 Medium

   Embedded KATNAL2 within the mammalian katanin interactome alongside KATNA1, KATNAL1, KATNB1, and KATNBL1, providing network context for its regulation.

   Evidence Affinity purification mass-spectrometry interactome (Katan-ome)

   PMID:26929214

   Open questions at the time

   • KATNAL2-specific functional follow-up limited
   • Stoichiometry and direct vs indirect contacts not resolved
4. 2017 High

   Demonstrated an in vivo requirement for KATNAL2 across distinct steps of spermatogenesis and pointed to δ-/ε-tubulin rather than canonical α-β polymers as its substrate, expanding katanin biology beyond classical microtubules.

   Evidence Mouse loss-of-function knockout with histological and cellular readouts plus co-localization/interaction studies

   PMID:29136647

   Open questions at the time

   • Direct enzymatic action on δ-/ε-tubulin not biochemically shown
   • When KATNAL2 acts with KATNB1 versus autonomously not defined
5. 2017 Medium

   Extended KATNAL2 function to neuronal development by showing it is needed for normal dendritic arborization.

   Evidence Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological readout

   PMID:27161796

   Open questions at the time

   • Single method/lab
   • Molecular mechanism linking microtubule severing to dendrite branching unknown
6. 2018 High

   Confirmed conserved KATNAL2 localization and ciliogenesis/brain-development function in a second vertebrate, generalizing the mammalian cell findings to whole-organism development.

   Evidence Morpholino knockdown, immunofluorescence, and phenotypic analysis in Xenopus embryos

   PMID:30096282

   Open questions at the time

   • Morpholino specificity not cross-validated genetically
   • Direct cause of brain phenotype (cilia vs neuron-intrinsic) not separated
7. 2020 Medium

   Mapped the structural basis of KATNAL2 targeting, showing the LisH-containing N-terminus governs dimerization, stability, and localization, with glutamylation-sensitive recruitment.

   Evidence Domain truncation/deletion with localization, dimerization, and stability assays in Tetrahymena

   PMID:31991798

   Open questions at the time

   • Ciliate ortholog may differ from mammalian protein
   • Catalytic AAA-domain activity not directly assayed
   • Glutamylation reader mechanism not defined
8. 2021 Low

   Consolidated the model that KATNAL2 regulates noncanonical δ-/ε-tubulin at the manchette, a non-centriolar microtubule structure.

   Evidence Co-localization and interaction findings synthesized in a review

   PMID:33867233

   Open questions at the time

   • Review synthesis rather than new primary data
   • Direct biochemical interaction with δ-/ε-tubulin not established here
9. 2024 High

   Established a causal mechanistic pathway from KATNAL2 loss to cerebral ventriculomegaly via disrupted ependymal cilia, planar cell polarity, and CSF flow, with cortical electrophysiological deficits and recapitulation by the ASD-associated F244L variant.

   Evidence Constitutive knockout and F244L knock-in mice with histology, cilia/PCP analysis, CSF flow assays, and electrophysiology

   PMID:38916997

   Open questions at the time

   • Molecular link between ciliary defect and neuronal excitability deficits unclear
   • Whether F244L is hypomorphic or dominant-negative not resolved
10. 2024 High

    Defined a developmental time window for KATNAL2 function by showing KO causes ciliary hyperfunction, progressive synaptic and behavioral deficits, and that early postnatal re-expression rescues all phenotypes, proving causality.

    Evidence Constitutive KO mouse, behavioral assays, ependymal cilia beat-frequency/length measurements, RNA-seq, and rescue by re-expression

    PMID:38718086

    Open questions at the time

    • Apparent ciliary hyperfunction here versus impaired ciliogenesis in cell studies not mechanistically reconciled
    • Cell-type responsible for behavioral rescue not pinpointed
11. 2025 Medium

    Identified TUBD1 (delta tubulin) as a functional partner of KATNAL2 and KATNB1 in manchette remodeling and sperm head shaping, cementing the noncanonical-tubulin module in spermatids.

    Evidence Conditional TUBD1 knockout mouse with manchette/sperm-head phenotyping and inferred co-functional partnership

    PMID:40586731

    Open questions at the time

    • Partnership inferred from phenocopy rather than direct biochemistry
    • Order of action within the KATNAL2-KATNB1-TUBD1 module unknown

• Direct biochemical demonstration of KATNAL2 microtubule-severing or ATPase activity, and reconciliation of its opposing ciliary phenotypes (impaired ciliogenesis in cells versus ependymal ciliary hyperfunction in vivo), remain unresolved.
• No in vitro reconstitution of severing activity in the corpus
• Substrate preference for δ-/ε-tubulin not biochemically proven
• Mechanism switching between negative and positive ciliary regulation undefined