{"gene":"WHAMM","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2010,"finding":"WHAMM is a nucleation-promoting factor (NPF) that activates the Arp2/3 complex via a C-terminal WCA module, and additionally engages microtubules and inhibits capping protein, activities not previously associated with canonical WCA-harboring proteins.","method":"Biochemical characterization, review of functional domain activities","journal":"Trends in cell biology","confidence":"High","confidence_rationale":"Tier 2 — independently replicated across labs, foundational review summarizing multiple orthogonal experimental findings","pmids":["20888769"],"is_preprint":false},{"year":2012,"finding":"WHAMM binds to the outer surface of microtubule protofilaments via a novel interaction between its central coiled-coil region and tubulin heterodimers; MT binding exposes the N-terminal membrane-binding domain at the MT periphery (enabling vesicle recruitment and tubulation) while masking the C-terminal WCA domain, thereby inhibiting actin nucleation.","method":"Cryo-electron microscopy, biophysical and biochemical assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure combined with biochemical validation of mutually exclusive MT-binding and actin-nucleation activities","pmids":["23027905"],"is_preprint":false},{"year":2015,"finding":"WHAMM directs Arp2/3 complex activity at the ER to promote autophagosome biogenesis via an actin comet tail mechanism; WHAMM puncta colocalize and comigrate with autophagy markers LC3, DFCP1, and p62, and knockdown of WHAMM or mutagenesis blocking its Arp2/3 interaction reduces autophagosome size and number.","method":"High-resolution live-cell imaging, siRNA knockdown, Arp2/3 inhibition, site-directed mutagenesis, co-localization with autophagy markers","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, mutagenesis, live imaging, chemical inhibition) in single study with strong controls","pmids":["26096974"],"is_preprint":false},{"year":2016,"finding":"Rab1 (an active, prenylated small G-protein) directly binds the N-terminal domain of WHAMM in vitro, recruits WHAMM to dynamic tubulovesicular structures, and stimulates WHAMM-associated membrane tubule formation, but paradoxically inhibits WHAMM-mediated actin assembly — a distinct regulatory strategy for membrane remodeling.","method":"In vitro binding assay with prenylated active Rab1, live-cell imaging, actin nucleation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding plus cellular imaging and functional actin assembly assay with multiple G-protein family members tested","pmids":["26823012"],"is_preprint":false},{"year":2017,"finding":"WHAMM interacts with αβ-tubulin through a small peptide motif (microtubule-binding motif, MBM) within its MT-binding domain; cryo-EM reconstruction of MBM assembled around MTs and chemical cross-linking/mass spectrometry revealed a conformational switch between non-MT-bound and MT-bound states.","method":"Cryo-electron microscopy, chemical cross-linking, mass spectrometry","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure plus cross-linking/MS validation","pmids":["28351611"],"is_preprint":false},{"year":2017,"finding":"WHAMM binds to the phospholipid PI(3)P and promotes actin nucleation at nascent autophagosomes; patient cells with a founder WHAMM mutation show severe autophagy defects, and re-introduction of wild-type WHAMM restores autophagosomal biogenesis and LC3 lipidation.","method":"Phospholipid-binding assay, patient cell complementation, LC3 lipidation assay, ubiquitinated protein aggregate clearance assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including direct lipid binding, genetic rescue, and functional autophagy readouts","pmids":["28720660"],"is_preprint":false},{"year":2019,"finding":"WHAMM is required for autophagic lysosome reformation (ALR); it is recruited to autolysosome membranes through specific interaction with PI(4,5)P2 and acts as an NPF to promote assembly of an actin scaffold on autolysosomes, driving tubulation during prolonged starvation.","method":"WHAMM knockout, phospholipid-binding assay (PI(4,5)P2 specificity), live imaging of autolysosome tubulation, actin scaffold visualization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific phenotype, direct lipid binding assay, and live imaging; multiple orthogonal methods","pmids":["31420534"],"is_preprint":false},{"year":2012,"finding":"WHAMM localizes around the meiotic spindle in mouse oocytes and is required for peripheral spindle migration, actin cap formation, and asymmetric cytokinesis; siRNA-mediated depletion of WHAMM disrupts spindle migration and reduces first polar body extrusion.","method":"Immunostaining, siRNA microinjection into oocytes, nocodazole/taxol treatment","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, but single lab, mouse oocyte model","pmids":["23160625"],"is_preprint":false},{"year":2021,"finding":"WHAMM (together with JMY) promotes the intrinsic apoptotic pathway downstream of p53 by enhancing mitochondrial permeabilization and caspase activation; WHAMM-mediated cell death can be opposed by the G-protein RhoD, whose upregulation upon JMY loss contributes to cell survival.","method":"WASP-family gene inactivation screen, caspase cleavage assays, cytochrome c release measurements, RhoD depletion/deletion experiments","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — systematic gene inactivation with multiple apoptotic readouts, but mechanism of WHAMM's direct contribution not fully resolved from JMY","pmids":["33872315"],"is_preprint":false},{"year":2021,"finding":"WHAMM co-localizes with the actin cage permeating the spindle in mouse oocytes and is essential for spindle formation, MTOC localization, and spindle actin assembly via Arp2/3 complex; WHAMM depletion causes chromosomal aneuploidy and abnormal asymmetric division.","method":"siRNA knockdown, immunofluorescence, brefeldin A treatment","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — KD with specific cellular phenotype, consistent with prior oocyte work, single lab","pmids":["33397186"],"is_preprint":false},{"year":2020,"finding":"WHAMM interaction with its target actin (required for autophagy initiation) is reduced in SETD2-null cells due to altered actin dynamics; this deficit is rescued by pharmacologic induction of actin polymerization with Jasplakinolide, indicating the WHAMM-actin interaction is sensitive to the polymerization state of actin rather than SETD2-mediated ActK68me3 directly.","method":"Co-immunoprecipitation, SETD2 knockout cells, pharmacologic rescue with Jasplakinolide, autophagy assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single Co-IP readout, indirect mechanistic inference","pmids":["33036756"],"is_preprint":false},{"year":2024,"finding":"WHAMM and its binding partner Arp2/3 complex control autophagosomal membrane closure and cargo receptor recruitment in mouse fibroblasts and human proximal tubule cells; WHAMM knockout in mice causes kidney proximal tubule dysfunction with accumulation of lipidated LC3, indicating a role for WHAMM-mediated actin assembly in autophagosome membrane remodeling and kidney nutrient reabsorption.","method":"WHAMM knockout mice, LC3 lipidation assay, autophagosome closure assay, cargo receptor recruitment assay, urine analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple orthogonal cellular and physiological readouts","pmids":["38598293"],"is_preprint":false},{"year":2025,"finding":"WHAMM controls cell death by regulating actin-mediated cytochrome c release from mitochondria and ASC speck formation; pharmacological inhibition of actin dynamics mitigates kidney disease in experimental models.","method":"Genetic deletion of Whamm in mice, cytochrome c release assay, ASC speck formation assay, pharmacologic actin inhibition in disease models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO plus mechanistic cell assays, single lab","pmids":["40138314"],"is_preprint":false},{"year":2024,"finding":"WHAMM promotes autophagic degradation of TGF-β1 by enhancing autophagosomal localization of TGF-β1 and promoting autophagy progression; WHAMM downregulation in hyperoxia-induced BPD leads to TGF-β1 accumulation and subsequent EMT in alveolar epithelial cells.","method":"WHAMM knockdown/overexpression, co-localization of TGF-β1 with autophagosome markers, autophagy flux assays","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic resolution of WHAMM's direct role vs. indirect autophagy effects","pmids":["39564703"],"is_preprint":false}],"current_model":"WHAMM is a Wiskott-Aldrich syndrome protein family nucleation-promoting factor that activates the Arp2/3 complex via its C-terminal WCA domain; its central coiled-coil region binds microtubule protofilaments (masking WCA activity), while its N-terminal domain recruits membranes through interactions with PI(3)P or PI(4,5)P2 and is regulated by direct binding to active Rab1, enabling WHAMM to coordinate microtubule-based vesicle trafficking and Arp2/3-driven actin assembly at the ER-Golgi interface, nascent autophagosomes, and autolysosomes to control autophagosome biogenesis, membrane closure, autophagic lysosome reformation, and mitochondrial cytochrome c release during apoptosis."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing WHAMM as a novel NPF with additional non-canonical activities — prior to this, WCA-domain proteins were not known to also bind microtubules or inhibit capping protein, so defining WHAMM's multifunctional domain architecture opened investigation of how actin nucleation could be coordinated with other cytoskeletal systems.","evidence":"Biochemical characterization and review of functional domain activities across multiple labs","pmids":["20888769"],"confidence":"High","gaps":["No structural detail on how microtubule binding and WCA activity are coordinated","Cellular contexts of WHAMM function undefined"]},{"year":2012,"claim":"Revealing how microtubule binding allosterically regulates WHAMM — cryo-EM showed that the coiled-coil region binds the outer surface of MT protofilaments, masking the WCA domain while exposing the N-terminal membrane-binding domain, establishing a structural basis for mutually exclusive actin nucleation and microtubule engagement.","evidence":"Cryo-EM reconstruction of WHAMM on MTs, biophysical and biochemical assays","pmids":["23027905"],"confidence":"High","gaps":["Atomic-resolution details of the WCA masking mechanism unresolved","In vivo validation of the conformational switch not yet performed"]},{"year":2012,"claim":"Identifying a role for WHAMM in meiotic spindle migration and asymmetric cell division — WHAMM localized around the meiotic spindle in mouse oocytes and its depletion disrupted spindle migration, actin cap formation, and polar body extrusion, extending WHAMM function beyond membrane trafficking.","evidence":"siRNA knockdown in mouse oocytes, immunostaining, nocodazole/taxol treatment","pmids":["23160625"],"confidence":"Medium","gaps":["Single-lab finding in one model system","Whether WHAMM acts via Arp2/3 in this context not directly tested","Relevance to mammalian fertility in vivo unknown"]},{"year":2015,"claim":"Connecting WHAMM-Arp2/3 activity to autophagosome biogenesis — live imaging showed WHAMM puncta colocalize with LC3/DFCP1/p62 and propel nascent autophagosomes via actin comet tails, and loss of WHAMM or its Arp2/3 interaction reduced autophagosome number and size, establishing WHAMM as a key actin-dependent regulator of autophagy initiation at the ER.","evidence":"High-resolution live-cell imaging, siRNA knockdown, Arp2/3 chemical inhibition, site-directed mutagenesis","pmids":["26096974"],"confidence":"High","gaps":["How WHAMM is initially recruited to omegasome membranes not defined","Relationship between comet-tail propulsion and autophagosome maturation unclear"]},{"year":2016,"claim":"Identifying Rab1 as a direct upstream regulator of WHAMM — active prenylated Rab1 binds the WHAMM N-terminal domain, recruits WHAMM to tubulovesicular structures, and stimulates membrane tubulation while inhibiting actin nucleation, revealing a regulatory mechanism that separates membrane remodeling from actin assembly.","evidence":"In vitro binding assay with prenylated active Rab1, live-cell imaging, actin nucleation assay testing multiple G-protein family members","pmids":["26823012"],"confidence":"High","gaps":["Downstream effectors of Rab1-WHAMM in membrane tubulation not identified","Whether Rab1 regulation operates during autophagy specifically is untested"]},{"year":2017,"claim":"Defining the molecular basis of WHAMM-microtubule interaction and identifying PI(3)P as the lipid signal recruiting WHAMM to autophagosomes — cryo-EM and cross-linking/MS mapped a minimal microtubule-binding motif that undergoes a conformational switch, while phospholipid assays showed PI(3)P binding directs WHAMM to nascent autophagosomes; patient cells with a founder WHAMM mutation showed severe autophagy defects rescued by wild-type WHAMM.","evidence":"Cryo-EM, chemical cross-linking/MS, phospholipid-binding assays, patient cell complementation, LC3 lipidation assays","pmids":["28351611","28720660"],"confidence":"High","gaps":["Identity and clinical phenotype of the founder WHAMM mutation not fully characterized at the organismal level","Structural basis of PI(3)P recognition by the N-terminal domain unresolved"]},{"year":2019,"claim":"Extending WHAMM function to autophagic lysosome reformation — WHAMM is recruited to autolysosome membranes via PI(4,5)P2 and assembles an actin scaffold that drives membrane tubulation during prolonged starvation, establishing that WHAMM acts at multiple stages of the autophagy pathway through distinct phosphoinositide interactions.","evidence":"WHAMM genetic knockout, PI(4,5)P2-binding assay, live imaging of autolysosome tubulation","pmids":["31420534"],"confidence":"High","gaps":["How WHAMM switches from PI(3)P recognition at autophagosomes to PI(4,5)P2 at autolysosomes is mechanistically unresolved","Whether ALR defects contribute to disease phenotypes unknown"]},{"year":2021,"claim":"Linking WHAMM to intrinsic apoptosis and oocyte spindle integrity — WHAMM (with JMY) promotes mitochondrial permeabilization and caspase activation downstream of p53, opposed by RhoD, and independently is required for spindle actin assembly and chromosome segregation fidelity in oocytes.","evidence":"WASP-family gene inactivation screen, caspase/cytochrome c assays, RhoD epistasis; siRNA knockdown in oocytes with immunofluorescence","pmids":["33872315","33397186"],"confidence":"Medium","gaps":["WHAMM's direct versus JMY-redundant contribution to apoptosis not fully separated","Whether WHAMM's apoptotic role requires Arp2/3 activation is untested","Mechanism by which WHAMM actin nucleation promotes mitochondrial permeabilization unresolved"]},{"year":2024,"claim":"Demonstrating in vivo physiological consequences of WHAMM loss — WHAMM knockout mice show defective autophagosome membrane closure, impaired cargo receptor recruitment, and kidney proximal tubule dysfunction with LC3 lipidation accumulation, and WHAMM promotes autophagic degradation of TGF-β1 in alveolar epithelial cells.","evidence":"WHAMM knockout mice, LC3 lipidation assays, autophagosome closure assays, urine analysis; WHAMM knockdown/overexpression with TGF-β1 co-localization in lung epithelial cells","pmids":["38598293","39564703"],"confidence":"High","gaps":["Full spectrum of organ phenotypes in WHAMM knockout mice not yet reported","Whether autophagosome closure defect is the proximate cause of kidney dysfunction or a parallel phenotype is uncertain"]},{"year":2025,"claim":"Establishing WHAMM as a regulator of actin-dependent cell death pathways with translational relevance — WHAMM controls cytochrome c release and ASC speck formation via actin dynamics, and pharmacological actin inhibition mitigates kidney disease in experimental models, connecting WHAMM-driven actin nucleation to inflammasome activation and tissue injury.","evidence":"Genetic Whamm deletion in mice, cytochrome c release and ASC speck assays, pharmacologic actin inhibition in disease models","pmids":["40138314"],"confidence":"Medium","gaps":["Whether ASC speck regulation is direct or secondary to mitochondrial damage is unclear","Therapeutic window and specificity of actin inhibition for WHAMM-driven pathology not defined"]},{"year":null,"claim":"The structural basis for how WHAMM discriminates between PI(3)P and PI(4,5)P2 at different autophagy stages, the precise mechanism by which WHAMM-nucleated actin promotes mitochondrial permeabilization and inflammasome activation, and whether WHAMM loss causes a recognizable human Mendelian disorder remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the N-terminal lipid-binding domain","Mechanism linking actin assembly to membrane closure at the molecular level unknown","No confirmed human disease gene–phenotype relationship beyond a single founder mutation study"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,4,7,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,4,7,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,12]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,5,6,11,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6]}],"complexes":[],"partners":["ACTR2","ACTR3","RAB1A","TUBA1A","TUBB"],"other_free_text":[]},"mechanistic_narrative":"WHAMM is a nucleation-promoting factor that coordinates Arp2/3-dependent actin assembly with microtubule-based membrane trafficking to drive autophagosome biogenesis, closure, and autophagic lysosome reformation. Its C-terminal WCA domain activates the Arp2/3 complex, while its central coiled-coil region binds microtubule protofilaments through a defined peptide motif, inducing a conformational switch that masks WCA activity and exposes the N-terminal membrane-binding domain for recruitment to PI(3)P-positive nascent autophagosomes or PI(4,5)P2-positive autolysosomes [PMID:23027905, PMID:28351611, PMID:28720660, PMID:31420534]. Active Rab1 directly binds the WHAMM N-terminal domain, recruits WHAMM to tubulovesicular membranes, and stimulates membrane tubulation while paradoxically inhibiting actin nucleation, providing a regulatory switch between membrane remodeling and actin assembly [PMID:26823012]. WHAMM also promotes intrinsic apoptosis by facilitating actin-dependent mitochondrial cytochrome c release and ASC speck formation, and WHAMM knockout in mice causes kidney proximal tubule dysfunction due to defective autophagosome membrane closure and cargo receptor recruitment [PMID:38598293, PMID:40138314]."},"prefetch_data":{"uniprot":{"accession":"Q8TF30","full_name":"WASP homolog-associated protein with actin, membranes and microtubules","aliases":["WAS protein homology region 2 domain-containing protein 1","WH2 domain-containing protein 1"],"length_aa":809,"mass_kda":90.9,"function":"Acts as a nucleation-promoting factor (NPF) that stimulates Arp2/3-mediated actin polymerization both at the Golgi apparatus and along tubular membranes. Its activity in membrane tubulation requires F-actin and interaction with microtubules. Proposed to use coordinated actin-nucleating and microtubule-binding activities of distinct WHAMM molecules to drive membrane tubule elongation; when MT-bound can recruit and remodel membrane vesicles but is prevented to activate the Arp2/3 complex. Involved as a regulator of Golgi positioning and morphology. Participates in vesicle transport between the reticulum endoplasmic and the Golgi complex. Required for RhoD-dependent actin reorganization such as in cell adhesion and cell migration","subcellular_location":"Cytoplasm; Endoplasmic reticulum-Golgi intermediate compartment; Cytoplasmic vesicle membrane; Golgi apparatus, cis-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q8TF30/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WHAMM","classification":"Not Classified","n_dependent_lines":145,"n_total_lines":1208,"dependency_fraction":0.12003311258278146},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WHAMM","total_profiled":1310},"omim":[{"mim_id":"616144","title":"WD REPEAT-CONTAINING PROTEIN 73; WDR73","url":"https://www.omim.org/entry/616144"},{"mim_id":"612393","title":"WAS PROTEIN HOMOLOG ASSOCIATED WITH ACTIN, GOLGI MEMBRANES, AND MICROTUBULES; WHAMM","url":"https://www.omim.org/entry/612393"},{"mim_id":"251300","title":"GALLOWAY-MOWAT SYNDROME 1; GAMOS1","url":"https://www.omim.org/entry/251300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":29.4}],"url":"https://www.proteinatlas.org/search/WHAMM"},"hgnc":{"alias_symbol":["KIAA1971","WHAMM1"],"prev_symbol":["WHDC1"]},"alphafold":{"accession":"Q8TF30","domains":[{"cath_id":"-","chopping":"182-372","consensus_level":"medium","plddt":92.9816,"start":182,"end":372},{"cath_id":"3.30.1520","chopping":"29-61_77-115_141-180","consensus_level":"high","plddt":80.8468,"start":29,"end":180},{"cath_id":"1.10.287","chopping":"382-420_457-508","consensus_level":"medium","plddt":93.7576,"start":382,"end":508}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF30","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF30-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF30-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WHAMM","jax_strain_url":"https://www.jax.org/strain/search?query=WHAMM"},"sequence":{"accession":"Q8TF30","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TF30.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TF30/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF30"}},"corpus_meta":[{"pmid":"20888769","id":"PMC_20888769","title":"WASH, WHAMM and JMY: regulation of Arp2/3 complex and beyond.","date":"2010","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20888769","citation_count":150,"is_preprint":false},{"pmid":"26096974","id":"PMC_26096974","title":"WHAMM Directs the Arp2/3 Complex to the ER for Autophagosome Biogenesis through an Actin Comet Tail Mechanism.","date":"2015","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26096974","citation_count":106,"is_preprint":false},{"pmid":"31420534","id":"PMC_31420534","title":"WHAMM initiates autolysosome tubulation by promoting actin polymerization on autolysosomes.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31420534","citation_count":59,"is_preprint":false},{"pmid":"22316129","id":"PMC_22316129","title":"Evolution of the eukaryotic ARP2/3 activators of the WASP family: WASP, WAVE, WASH, and WHAMM, and the proposed new family members WAWH and WAML.","date":"2012","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/22316129","citation_count":52,"is_preprint":false},{"pmid":"23027905","id":"PMC_23027905","title":"Structural insights into WHAMM-mediated cytoskeletal coordination during membrane remodeling.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23027905","citation_count":28,"is_preprint":false},{"pmid":"26823012","id":"PMC_26823012","title":"Rab1 recruits WHAMM during membrane remodeling but limits actin nucleation.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26823012","citation_count":27,"is_preprint":false},{"pmid":"26291929","id":"PMC_26291929","title":"WHAMM links actin assembly via the Arp2/3 complex to autophagy.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26291929","citation_count":24,"is_preprint":false},{"pmid":"28720660","id":"PMC_28720660","title":"An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28720660","citation_count":21,"is_preprint":false},{"pmid":"23160625","id":"PMC_23160625","title":"WHAMM is required for meiotic spindle migration and asymmetric cytokinesis in mouse oocytes.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23160625","citation_count":18,"is_preprint":false},{"pmid":"33872315","id":"PMC_33872315","title":"The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33872315","citation_count":12,"is_preprint":false},{"pmid":"28351611","id":"PMC_28351611","title":"Structural Insights of WHAMM's Interaction with Microtubules by Cryo-EM.","date":"2017","source":"Journal of molecular 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/38598293","citation_count":3,"is_preprint":false},{"pmid":"40138314","id":"PMC_40138314","title":"The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40138314","citation_count":1,"is_preprint":false},{"pmid":"38328079","id":"PMC_38328079","title":"WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38328079","citation_count":1,"is_preprint":false},{"pmid":"39564703","id":"PMC_39564703","title":"WHAMM Inhibits Type II Alveolar Epithelial Cell EMT by Mediating Autophagic Degradation of TGF-β1 in Bronchopulmonary Dysplasia.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39564703","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8368,"output_tokens":3211,"usd":0.036635},"stage2":{"model":"claude-opus-4-6","input_tokens":6613,"output_tokens":3180,"usd":0.168848},"total_usd":0.205483,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"WHAMM is a nucleation-promoting factor (NPF) that activates the Arp2/3 complex via a C-terminal WCA module, and additionally engages microtubules and inhibits capping protein, activities not previously associated with canonical WCA-harboring proteins.\",\n      \"method\": \"Biochemical characterization, review of functional domain activities\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independently replicated across labs, foundational review summarizing multiple orthogonal experimental findings\",\n      \"pmids\": [\"20888769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WHAMM binds to the outer surface of microtubule protofilaments via a novel interaction between its central coiled-coil region and tubulin heterodimers; MT binding exposes the N-terminal membrane-binding domain at the MT periphery (enabling vesicle recruitment and tubulation) while masking the C-terminal WCA domain, thereby inhibiting actin nucleation.\",\n      \"method\": \"Cryo-electron microscopy, biophysical and biochemical assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure combined with biochemical validation of mutually exclusive MT-binding and actin-nucleation activities\",\n      \"pmids\": [\"23027905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WHAMM directs Arp2/3 complex activity at the ER to promote autophagosome biogenesis via an actin comet tail mechanism; WHAMM puncta colocalize and comigrate with autophagy markers LC3, DFCP1, and p62, and knockdown of WHAMM or mutagenesis blocking its Arp2/3 interaction reduces autophagosome size and number.\",\n      \"method\": \"High-resolution live-cell imaging, siRNA knockdown, Arp2/3 inhibition, site-directed mutagenesis, co-localization with autophagy markers\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, mutagenesis, live imaging, chemical inhibition) in single study with strong controls\",\n      \"pmids\": [\"26096974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab1 (an active, prenylated small G-protein) directly binds the N-terminal domain of WHAMM in vitro, recruits WHAMM to dynamic tubulovesicular structures, and stimulates WHAMM-associated membrane tubule formation, but paradoxically inhibits WHAMM-mediated actin assembly — a distinct regulatory strategy for membrane remodeling.\",\n      \"method\": \"In vitro binding assay with prenylated active Rab1, live-cell imaging, actin nucleation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding plus cellular imaging and functional actin assembly assay with multiple G-protein family members tested\",\n      \"pmids\": [\"26823012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WHAMM interacts with αβ-tubulin through a small peptide motif (microtubule-binding motif, MBM) within its MT-binding domain; cryo-EM reconstruction of MBM assembled around MTs and chemical cross-linking/mass spectrometry revealed a conformational switch between non-MT-bound and MT-bound states.\",\n      \"method\": \"Cryo-electron microscopy, chemical cross-linking, mass spectrometry\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure plus cross-linking/MS validation\",\n      \"pmids\": [\"28351611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WHAMM binds to the phospholipid PI(3)P and promotes actin nucleation at nascent autophagosomes; patient cells with a founder WHAMM mutation show severe autophagy defects, and re-introduction of wild-type WHAMM restores autophagosomal biogenesis and LC3 lipidation.\",\n      \"method\": \"Phospholipid-binding assay, patient cell complementation, LC3 lipidation assay, ubiquitinated protein aggregate clearance assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including direct lipid binding, genetic rescue, and functional autophagy readouts\",\n      \"pmids\": [\"28720660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WHAMM is required for autophagic lysosome reformation (ALR); it is recruited to autolysosome membranes through specific interaction with PI(4,5)P2 and acts as an NPF to promote assembly of an actin scaffold on autolysosomes, driving tubulation during prolonged starvation.\",\n      \"method\": \"WHAMM knockout, phospholipid-binding assay (PI(4,5)P2 specificity), live imaging of autolysosome tubulation, actin scaffold visualization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific phenotype, direct lipid binding assay, and live imaging; multiple orthogonal methods\",\n      \"pmids\": [\"31420534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WHAMM localizes around the meiotic spindle in mouse oocytes and is required for peripheral spindle migration, actin cap formation, and asymmetric cytokinesis; siRNA-mediated depletion of WHAMM disrupts spindle migration and reduces first polar body extrusion.\",\n      \"method\": \"Immunostaining, siRNA microinjection into oocytes, nocodazole/taxol treatment\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, but single lab, mouse oocyte model\",\n      \"pmids\": [\"23160625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WHAMM (together with JMY) promotes the intrinsic apoptotic pathway downstream of p53 by enhancing mitochondrial permeabilization and caspase activation; WHAMM-mediated cell death can be opposed by the G-protein RhoD, whose upregulation upon JMY loss contributes to cell survival.\",\n      \"method\": \"WASP-family gene inactivation screen, caspase cleavage assays, cytochrome c release measurements, RhoD depletion/deletion experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic gene inactivation with multiple apoptotic readouts, but mechanism of WHAMM's direct contribution not fully resolved from JMY\",\n      \"pmids\": [\"33872315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WHAMM co-localizes with the actin cage permeating the spindle in mouse oocytes and is essential for spindle formation, MTOC localization, and spindle actin assembly via Arp2/3 complex; WHAMM depletion causes chromosomal aneuploidy and abnormal asymmetric division.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, brefeldin A treatment\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with specific cellular phenotype, consistent with prior oocyte work, single lab\",\n      \"pmids\": [\"33397186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WHAMM interaction with its target actin (required for autophagy initiation) is reduced in SETD2-null cells due to altered actin dynamics; this deficit is rescued by pharmacologic induction of actin polymerization with Jasplakinolide, indicating the WHAMM-actin interaction is sensitive to the polymerization state of actin rather than SETD2-mediated ActK68me3 directly.\",\n      \"method\": \"Co-immunoprecipitation, SETD2 knockout cells, pharmacologic rescue with Jasplakinolide, autophagy assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single Co-IP readout, indirect mechanistic inference\",\n      \"pmids\": [\"33036756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WHAMM and its binding partner Arp2/3 complex control autophagosomal membrane closure and cargo receptor recruitment in mouse fibroblasts and human proximal tubule cells; WHAMM knockout in mice causes kidney proximal tubule dysfunction with accumulation of lipidated LC3, indicating a role for WHAMM-mediated actin assembly in autophagosome membrane remodeling and kidney nutrient reabsorption.\",\n      \"method\": \"WHAMM knockout mice, LC3 lipidation assay, autophagosome closure assay, cargo receptor recruitment assay, urine analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal cellular and physiological readouts\",\n      \"pmids\": [\"38598293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WHAMM controls cell death by regulating actin-mediated cytochrome c release from mitochondria and ASC speck formation; pharmacological inhibition of actin dynamics mitigates kidney disease in experimental models.\",\n      \"method\": \"Genetic deletion of Whamm in mice, cytochrome c release assay, ASC speck formation assay, pharmacologic actin inhibition in disease models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO plus mechanistic cell assays, single lab\",\n      \"pmids\": [\"40138314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WHAMM promotes autophagic degradation of TGF-β1 by enhancing autophagosomal localization of TGF-β1 and promoting autophagy progression; WHAMM downregulation in hyperoxia-induced BPD leads to TGF-β1 accumulation and subsequent EMT in alveolar epithelial cells.\",\n      \"method\": \"WHAMM knockdown/overexpression, co-localization of TGF-β1 with autophagosome markers, autophagy flux assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic resolution of WHAMM's direct role vs. indirect autophagy effects\",\n      \"pmids\": [\"39564703\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WHAMM is a Wiskott-Aldrich syndrome protein family nucleation-promoting factor that activates the Arp2/3 complex via its C-terminal WCA domain; its central coiled-coil region binds microtubule protofilaments (masking WCA activity), while its N-terminal domain recruits membranes through interactions with PI(3)P or PI(4,5)P2 and is regulated by direct binding to active Rab1, enabling WHAMM to coordinate microtubule-based vesicle trafficking and Arp2/3-driven actin assembly at the ER-Golgi interface, nascent autophagosomes, and autolysosomes to control autophagosome biogenesis, membrane closure, autophagic lysosome reformation, and mitochondrial cytochrome c release during apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WHAMM is a nucleation-promoting factor that coordinates Arp2/3-dependent actin assembly with microtubule-based membrane trafficking to drive autophagosome biogenesis, closure, and autophagic lysosome reformation. Its C-terminal WCA domain activates the Arp2/3 complex, while its central coiled-coil region binds microtubule protofilaments through a defined peptide motif, inducing a conformational switch that masks WCA activity and exposes the N-terminal membrane-binding domain for recruitment to PI(3)P-positive nascent autophagosomes or PI(4,5)P2-positive autolysosomes [PMID:23027905, PMID:28351611, PMID:28720660, PMID:31420534]. Active Rab1 directly binds the WHAMM N-terminal domain, recruits WHAMM to tubulovesicular membranes, and stimulates membrane tubulation while paradoxically inhibiting actin nucleation, providing a regulatory switch between membrane remodeling and actin assembly [PMID:26823012]. WHAMM also promotes intrinsic apoptosis by facilitating actin-dependent mitochondrial cytochrome c release and ASC speck formation, and WHAMM knockout in mice causes kidney proximal tubule dysfunction due to defective autophagosome membrane closure and cargo receptor recruitment [PMID:38598293, PMID:40138314].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing WHAMM as a novel NPF with additional non-canonical activities — prior to this, WCA-domain proteins were not known to also bind microtubules or inhibit capping protein, so defining WHAMM's multifunctional domain architecture opened investigation of how actin nucleation could be coordinated with other cytoskeletal systems.\",\n      \"evidence\": \"Biochemical characterization and review of functional domain activities across multiple labs\",\n      \"pmids\": [\"20888769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural detail on how microtubule binding and WCA activity are coordinated\", \"Cellular contexts of WHAMM function undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealing how microtubule binding allosterically regulates WHAMM — cryo-EM showed that the coiled-coil region binds the outer surface of MT protofilaments, masking the WCA domain while exposing the N-terminal membrane-binding domain, establishing a structural basis for mutually exclusive actin nucleation and microtubule engagement.\",\n      \"evidence\": \"Cryo-EM reconstruction of WHAMM on MTs, biophysical and biochemical assays\",\n      \"pmids\": [\"23027905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution details of the WCA masking mechanism unresolved\", \"In vivo validation of the conformational switch not yet performed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying a role for WHAMM in meiotic spindle migration and asymmetric cell division — WHAMM localized around the meiotic spindle in mouse oocytes and its depletion disrupted spindle migration, actin cap formation, and polar body extrusion, extending WHAMM function beyond membrane trafficking.\",\n      \"evidence\": \"siRNA knockdown in mouse oocytes, immunostaining, nocodazole/taxol treatment\",\n      \"pmids\": [\"23160625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding in one model system\", \"Whether WHAMM acts via Arp2/3 in this context not directly tested\", \"Relevance to mammalian fertility in vivo unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connecting WHAMM-Arp2/3 activity to autophagosome biogenesis — live imaging showed WHAMM puncta colocalize with LC3/DFCP1/p62 and propel nascent autophagosomes via actin comet tails, and loss of WHAMM or its Arp2/3 interaction reduced autophagosome number and size, establishing WHAMM as a key actin-dependent regulator of autophagy initiation at the ER.\",\n      \"evidence\": \"High-resolution live-cell imaging, siRNA knockdown, Arp2/3 chemical inhibition, site-directed mutagenesis\",\n      \"pmids\": [\"26096974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WHAMM is initially recruited to omegasome membranes not defined\", \"Relationship between comet-tail propulsion and autophagosome maturation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying Rab1 as a direct upstream regulator of WHAMM — active prenylated Rab1 binds the WHAMM N-terminal domain, recruits WHAMM to tubulovesicular structures, and stimulates membrane tubulation while inhibiting actin nucleation, revealing a regulatory mechanism that separates membrane remodeling from actin assembly.\",\n      \"evidence\": \"In vitro binding assay with prenylated active Rab1, live-cell imaging, actin nucleation assay testing multiple G-protein family members\",\n      \"pmids\": [\"26823012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of Rab1-WHAMM in membrane tubulation not identified\", \"Whether Rab1 regulation operates during autophagy specifically is untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the molecular basis of WHAMM-microtubule interaction and identifying PI(3)P as the lipid signal recruiting WHAMM to autophagosomes — cryo-EM and cross-linking/MS mapped a minimal microtubule-binding motif that undergoes a conformational switch, while phospholipid assays showed PI(3)P binding directs WHAMM to nascent autophagosomes; patient cells with a founder WHAMM mutation showed severe autophagy defects rescued by wild-type WHAMM.\",\n      \"evidence\": \"Cryo-EM, chemical cross-linking/MS, phospholipid-binding assays, patient cell complementation, LC3 lipidation assays\",\n      \"pmids\": [\"28351611\", \"28720660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and clinical phenotype of the founder WHAMM mutation not fully characterized at the organismal level\", \"Structural basis of PI(3)P recognition by the N-terminal domain unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending WHAMM function to autophagic lysosome reformation — WHAMM is recruited to autolysosome membranes via PI(4,5)P2 and assembles an actin scaffold that drives membrane tubulation during prolonged starvation, establishing that WHAMM acts at multiple stages of the autophagy pathway through distinct phosphoinositide interactions.\",\n      \"evidence\": \"WHAMM genetic knockout, PI(4,5)P2-binding assay, live imaging of autolysosome tubulation\",\n      \"pmids\": [\"31420534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WHAMM switches from PI(3)P recognition at autophagosomes to PI(4,5)P2 at autolysosomes is mechanistically unresolved\", \"Whether ALR defects contribute to disease phenotypes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking WHAMM to intrinsic apoptosis and oocyte spindle integrity — WHAMM (with JMY) promotes mitochondrial permeabilization and caspase activation downstream of p53, opposed by RhoD, and independently is required for spindle actin assembly and chromosome segregation fidelity in oocytes.\",\n      \"evidence\": \"WASP-family gene inactivation screen, caspase/cytochrome c assays, RhoD epistasis; siRNA knockdown in oocytes with immunofluorescence\",\n      \"pmids\": [\"33872315\", \"33397186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WHAMM's direct versus JMY-redundant contribution to apoptosis not fully separated\", \"Whether WHAMM's apoptotic role requires Arp2/3 activation is untested\", \"Mechanism by which WHAMM actin nucleation promotes mitochondrial permeabilization unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating in vivo physiological consequences of WHAMM loss — WHAMM knockout mice show defective autophagosome membrane closure, impaired cargo receptor recruitment, and kidney proximal tubule dysfunction with LC3 lipidation accumulation, and WHAMM promotes autophagic degradation of TGF-β1 in alveolar epithelial cells.\",\n      \"evidence\": \"WHAMM knockout mice, LC3 lipidation assays, autophagosome closure assays, urine analysis; WHAMM knockdown/overexpression with TGF-β1 co-localization in lung epithelial cells\",\n      \"pmids\": [\"38598293\", \"39564703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of organ phenotypes in WHAMM knockout mice not yet reported\", \"Whether autophagosome closure defect is the proximate cause of kidney dysfunction or a parallel phenotype is uncertain\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing WHAMM as a regulator of actin-dependent cell death pathways with translational relevance — WHAMM controls cytochrome c release and ASC speck formation via actin dynamics, and pharmacological actin inhibition mitigates kidney disease in experimental models, connecting WHAMM-driven actin nucleation to inflammasome activation and tissue injury.\",\n      \"evidence\": \"Genetic Whamm deletion in mice, cytochrome c release and ASC speck assays, pharmacologic actin inhibition in disease models\",\n      \"pmids\": [\"40138314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ASC speck regulation is direct or secondary to mitochondrial damage is unclear\", \"Therapeutic window and specificity of actin inhibition for WHAMM-driven pathology not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how WHAMM discriminates between PI(3)P and PI(4,5)P2 at different autophagy stages, the precise mechanism by which WHAMM-nucleated actin promotes mitochondrial permeabilization and inflammasome activation, and whether WHAMM loss causes a recognizable human Mendelian disorder remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the N-terminal lipid-binding domain\", \"Mechanism linking actin assembly to membrane closure at the molecular level unknown\", \"No confirmed human disease gene–phenotype relationship beyond a single founder mutation study\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 4, 7, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 4, 7, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 5, 6, 11, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACTR2\",\n      \"ACTR3\",\n      \"RAB1A\",\n      \"TUBA1A\",\n      \"TUBB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}