Affinage

KLHL17

Kelch-like protein 17 · UniProt Q6TDP4

Length
642 aa
Mass
69.9 kDa
Annotated
2026-06-10
10 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLHL17 (Actinfilin) is a brain-enriched, actin-associated adaptor protein that governs activity-dependent dendritic spine enlargement and synaptic function (PMID:33256713). It localizes to circular puncta in dendritic spines adjacent to F-actin, and both its N-terminal BTB and C-terminal Kelch domains are required to drive F-actin enrichment and spine enlargement, with its loss reducing synaptic markers and altering mEPSC profiles (PMID:33256713). KLHL17 functions as a CUL3 ubiquitin ligase adaptor and operates through at least two receptor-directed mechanisms: it stabilizes NSF to support surface AMPAR expression, and it mediates activity-dependent degradation of the kainate receptor subunit GluK2, which otherwise contributes to excess calcium influx and impaired spine enlargement when degradation fails (PMID:38898681). KLHL17 expression is itself regulated by neuronal activity, and it controls the synaptic distribution of synaptopodin (SYNPO), positioning the spine apparatus (an ER compartment) within spines; disrupting the KLHL17–SYNPO association phenocopies KLHL17 loss, impairing calcium events, activity-dependent spine enlargement, and downstream ERK phosphorylation and C-FOS induction (PMID:37651441). In non-neuronal contexts, KLHL17 has been identified as a component of Cullin-E3 ubiquitin ligase complexes (PMID:40307206) and promotes proliferation and migration via Ras/MAPK signaling in cancer cell lines (PMID:35978057).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2020 High

    Established KLHL17 as a domain-dependent regulator of actin remodeling and dendritic spine morphology, defining its core synaptic function before any molecular partners were known.

    Evidence Immunostaining, knockdown/knockout, domain-deletion mapping (BTB-only, Kelch-only), mEPSC recording and behavioral assays in hippocampal neurons and mice

    PMID:33256713

    Open questions at the time
    • Molecular partners mediating F-actin remodeling not identified
    • Whether spine enlargement depends on ubiquitin ligase activity not yet addressed
    • Mechanism linking BTB/Kelch domains to actin not defined
  2. 2023 High

    Connected KLHL17 to the spine apparatus by showing it controls synaptopodin distribution, explaining how it gates activity-dependent spine enlargement and downstream signaling.

    Evidence Mouse haploinsufficiency/knockout, super-resolution expansion microscopy, calcium imaging, ERK/C-FOS readouts, and genetic disruption of the KLHL17–SYNPO interaction

    PMID:37651441

    Open questions at the time
    • Whether KLHL17 ubiquitinates SYNPO or acts non-catalytically unclear
    • Direct biochemical nature of the KLHL17–SYNPO association not resolved
    • How activity regulates KLHL17 expression not defined
  3. 2024 High

    Identified two distinct receptor-directed mechanisms — NSF stabilization for AMPAR surface trafficking and CUL3-dependent GluK2 degradation — establishing KLHL17 as a ubiquitin ligase adaptor coupling receptor handling to spine enlargement.

    Evidence Proteomics, surface biotinylation, knockdown/knockout in hippocampal neurons, calcium imaging, and CUL3 complex biochemistry

    PMID:38898681

    Open questions at the time
    • Mechanism by which KLHL17 stabilizes rather than degrades NSF unclear
    • Direct ubiquitination of GluK2 versus indirect effect not fully resolved
    • How the NSF and GluK2 arms are coordinated within one adaptor unknown
  4. 2024 Medium

    Extended KLHL17 beyond neurons by placing it in Cullin-E3 ligase complexes in cancer cells with candidate cytoskeletal substrates, suggesting a broader adaptor role.

    Evidence Mass spectrometry proteomics in PDAC-derived cells

    PMID:40307206

    Open questions at the time
    • Vimentin and nestin substrates not biochemically validated
    • Single proteomic identification without functional follow-up
    • Relevance to PDAC biology untested
  5. 2022 Medium

    Linked KLHL17 to Ras/MAPK-driven proliferation and migration in lung cancer cells, indicating a pro-tumorigenic signaling role distinct from its neuronal function.

    Evidence Overexpression, siRNA knockdown, salirasib Ras inhibition, proliferation/migration assays and pathway western blots in NSCLC cell lines

    PMID:35978057

    Open questions at the time
    • Pathway placement is phenotypic/correlative without a direct biochemical substrate
    • Whether ubiquitin ligase activity drives the Ras/MAPK effect unknown
    • Direct molecular link between KLHL17 and Ras not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KLHL17's ubiquitin ligase adaptor activity is mechanistically integrated across its multiple targets (NSF, GluK2, SYNPO) and reconciled between neuronal and oncogenic contexts remains unresolved.
  • No unifying model linking actin remodeling, receptor trafficking, and ER clustering
  • No structural characterization of the BTB/Kelch–CUL3 assembly in any context
  • Direct ubiquitination substrates not comprehensively validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005856 cytoskeleton 1
Partners
CUL3GLUK2NSFSYNPO
Complex memberships
CUL3 ubiquitin ligase complexCullin-E3 ubiquitin ligase complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 KLHL17/Actinfilin localizes to circular puncta in dendritic spines adjacent to F-actin and is required for F-actin enrichment and dendritic spine enlargement (but not spine density or length). Both the N-terminal BTB domain and C-terminal Kelch domains are required for F-actin remodeling at spines. Klhl17 knockout/knockdown reduces postsynaptic and presynaptic markers and alters mEPSC profiles, indicating impaired synaptic activity. Fluorescent immunostaining, knockdown/knockout in cultured hippocampal neurons, expression of truncated fragments (BTB-only, Kelch-only), electrophysiological recording (mEPSC), mouse behavioral assays Journal of biomedical science High 33256713
2023 KLHL17 expression is regulated by neuronal activity and KLHL17 controls the synaptic distribution of synaptopodin (SYNPO), a marker of the spine apparatus (a specialized ER compartment in dendritic spines). Super-resolution expansion microscopy shows KLHL17 is closely adjacent to the ER/SYNPO complex. Klhl17 haploinsufficiency and knockout reduce the proportion of dendritic spines containing ER clusters and alter calcium events at spines, impairing activity-dependent spine enlargement and neuronal activation (ERK phosphorylation, C-FOS expression). Disrupting the KLHL17–SYNPO association phenocopies Klhl17 loss. Mouse genetic models (haploinsufficiency, knockout), super-resolution expansion microscopy, calcium imaging, ERK phosphorylation/C-FOS immunostaining, genetic disruption of KLHL17–SYNPO interaction PLoS biology High 37651441
2024 KLHL17 interacts with N-ethylmaleimide-sensitive fusion protein (NSF) in neurons (identified by proteomics); this interaction stabilizes NSF protein levels. Consistent with NSF's role in AMPAR surface trafficking, Klhl17 deficiency reduces surface (but not total) AMPAR expression and impairs synaptic F-actin distribution and dendritic spine enlargement via the NSF pathway. Separately, KLHL17 acts as a CUL3 ubiquitin ligase adaptor to mediate activity-dependent degradation of the kainate receptor subunit GluK2; Klhl17 deficiency impairs GluK2 degradation and GluK2 contributes to increased calcium influx amplitude and to dendritic spine enlargement defects in Klhl17-deficient neurons. Proteomics (KLHL17–NSF interaction), surface biotinylation (AMPAR surface expression), knockdown/knockout in hippocampal neurons, calcium imaging, CUL3 complex biochemistry Journal of neurochemistry High 38898681
2024 Proteomic analysis in PDAC-derived cells identifies KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex, with vimentin and nestin as candidate substrates for degradation. Proteomic analysis (mass spectrometry) in PDAC-derived cells Nature communications Medium 40307206
2022 Overexpression of KLHL17 in NSCLC cell lines promotes proliferation and migration with elevated Ras/MAPK signaling and increased cyclin D1, CDK4, MMP2, and RhoA; KLHL17 knockdown suppresses these effects. Treatment with Ras inhibitor salirasib prevents KLHL17-induced Ras/MAPK activity and tumor proliferation/migration, placing KLHL17 upstream of Ras/MAPK in this cellular context. KLHL17-Flag overexpression, siRNA knockdown, Ras inhibitor (salirasib) treatment, proliferation/migration assays, western blotting for pathway markers in NSCLC cell lines Laboratory investigation Medium 35978057

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. European journal of human genetics : EJHG 67 21694734
2022 Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the Ras/MAPK signaling pathway. Laboratory investigation; a journal of technical methods and pathology 20 35978057
2017 Deconvolution of DNA methylation identifies differentially methylated gene regions on 1p36 across breast cancer subtypes. Scientific reports 20 28912426
2020 KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement. Journal of biomedical science 13 33256713
2023 Autism-related KLHL17 and SYNPO act in concert to control activity-dependent dendritic spine enlargement and the spine apparatus. PLoS biology 9 37651441
2025 Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33. Nature communications 4 40307206
2024 KLHL17 differentially controls the expression of AMPA- and KA-type glutamate receptors to regulate dendritic spine enlargement. Journal of neurochemistry 3 38898681
2024 Rapid Identification of Ancient Leather Species Using an Enzyme-Linked Immunosorbent Assay Based on Proteomic and Evolutionary Analyses. Journal of proteome research 2 39585938
2026 Service Year-Dependent Disruption of Reproductive Hormones and Altered DNA Methylation in Male Firefighters. Journal of occupational and environmental medicine 0 42262377
2024 Allelic effects on KLHL17 expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33. medRxiv : the preprint server for health sciences 0 39371158

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