{"gene":"MAL","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1995,"finding":"VIP17/MAL (canine homolog of human MAL proteolipid) localizes to apical transport vesicles in MDCK cells, cycling between the Golgi complex and the apical plasma membrane, consistent with a role as a component of the vesicular trafficking machinery for apical sorting.","method":"Immunofluorescence microscopy of epitope-tagged VIP17/MAL in BHK and MDCK cells; subcellular fractionation; biochemical enrichment in CHAPS-insoluble complexes","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with subcellular fractionation, single lab","pmids":["8549777"],"is_preprint":false},{"year":1995,"finding":"MVP17, the rat oligodendrocyte homolog of human MAL (88.9% identity), is expressed specifically in oligodendrocytes and brain during active myelination and is enriched in detergent-insoluble protein-lipid complexes, indicating association with glycolipid-rich microdomains during myelinogenesis.","method":"Protein microsequencing, cDNA cloning, Northern analysis, in vitro translation, two-dimensional gel electrophoresis of detergent-insoluble fractions","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation plus molecular cloning, single lab","pmids":["8583510"],"is_preprint":false},{"year":1997,"finding":"MAL and caveolin occupy distinct lipid microenvironments within internal detergent-insoluble membranes of MDCK cells; MAL resides in an internal glycolipid-enriched microdomain independently of caveolin expression, demonstrating heterogeneity within the raft compartment.","method":"Sucrose-gradient fractionation of Triton X-100 cell extracts; immunofluorescence in MDCK, Jurkat, and A498 cells; detergent-solubilization assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — orthogonal biochemical and imaging methods, single lab","pmids":["9168919"],"is_preprint":false},{"year":1997,"finding":"MAL is identified as a member of an extended gene family that includes plasmolipin, BENE, and other tetraspan proteins; the conserved fingerprint motif -[Q/Y-G-W-V-M-F/Y-V]- at the first extracellular loop/second transmembrane domain junction defines the MAL protein family.","method":"Mouse MAL cDNA cloning and structural gene characterization; database searches and computer-aided sequence analysis; Northern blot expression analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning with sequence-based family definition, single lab","pmids":["9168137"],"is_preprint":false},{"year":1998,"finding":"MAL associates with GPI-anchored proteins and Src-like tyrosine kinases (including Lck) in glycolipid-enriched membrane (GEM) microdomains of T lymphocytes; co-immunoprecipitation with anti-MAL and anti-CD59 antibodies demonstrated specific association in both cell lines and primary T cells, and MAL and Lck co-localize in endosomal GEM fractions.","method":"Monoclonal antibody generation against MAL; co-immunoprecipitation; sucrose-gradient fractionation of GEM microdomains from HPB-ALL and primary human T lymphocytes","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — reciprocal co-IP in two cell types, single lab","pmids":["9842910"],"is_preprint":false},{"year":1998,"finding":"A C-terminal tetrapeptide motif LIRW is necessary for incorporation of MAL into glycolipid-enriched membrane (GEM) microdomains; the arginine within LIRW is the most critical residue, and loss of GEM incorporation correlates with loss of brefeldin A sensitivity, linking GEM association to Golgi-dependent transport function.","method":"Site-directed mutagenesis of MAL C-terminus; pulse-chase experiments; sucrose-gradient fractionation of GEM fractions; brefeldin A treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with defined sorting motif and functional consequence, single lab with multiple orthogonal methods","pmids":["9582298"],"is_preprint":false},{"year":1999,"finding":"MAL is necessary for both normal apical transport rate and accurate sorting of influenza virus hemagglutinin (HA) to the apical surface of MDCK cells; MAL depletion reduces HA association with GEMs, slows surface delivery, inhibits apical delivery, and causes partial basolateral missorting; these defects are rescued by ectopic MAL re-expression.","method":"Antisense oligonucleotide-based MAL depletion; ectopic MAL expression rescue; surface biotinylation; domain-specific transport assays; monoclonal antibody to canine MAL","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with rescue, multiple cargo readouts, single lab","pmids":["10189374"],"is_preprint":false},{"year":1999,"finding":"Overexpression of VIP17/MAL in MDCK cells increases apical delivery and expands the apical surface domain; antisense-mediated knockdown causes Golgi accumulation and impaired apical transport of multiple apical markers (HA, clusterin/gp80, gp114, GPI-anchored protein) without affecting basolateral E-cadherin distribution, establishing MAL as a component of the apical sorting machinery that operates via sphingolipid-cholesterol rafts.","method":"Stable over-expression and antisense RNA expression in MDCK cells; immunofluorescence; domain-selective transport assays for multiple cargo proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation (OE and KD) with multiple cargo readouts, replicated across cargo types","pmids":["10339572"],"is_preprint":false},{"year":1999,"finding":"MAL is an itinerant protein that cycles between the trans-Golgi network (TGN) and the plasma membrane; surface-expressed MAL is rapidly internalized via an endosomal pathway requiring endosomal acidification, and approximately 30% of internalized MAL is recycled back to the TGN, consistent with a role as a reusable component of the apical transport machinery.","method":"FLAG-epitope and O-glycosylation tag insertion into MAL extracellular loop; surface biotinylation; anti-FLAG surface binding; neuraminidase sensitivity; resialylation assays; flow cytometry; chloroquine/monensin/NH4Cl inhibition","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal approaches (biotinylation, glycan chemistry, pharmacological inhibition) establishing itinerant trafficking cycle, single lab","pmids":["10512878"],"is_preprint":false},{"year":2000,"finding":"MAL co-purifies with specific glycosphingolipids (galactosylceramide and sulfatide) in detergent-insoluble domains in myelin and epithelial cells, indicating a close functional association with glycosphingolipid-enriched microdomains; MAL is localized to compact myelin in the nervous system and to the apical plasma membrane in kidney and stomach epithelial cells.","method":"Biochemical co-purification with detergent-resistant membranes; immunolocalization in multiple tissues","journal":"Progress in neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 — biochemical co-fractionation and immunolocalization, review synthesizing multiple studies","pmids":["10739088"],"is_preprint":false},{"year":2003,"finding":"Features required for HA apical sorting in MDCK cells differ from those required for DRM association or MAL co-precipitation; mutations in HA transmembrane residues that prevent DRM association also decrease MAL co-precipitation, but DRM association is not sufficient for apical sorting; the limited extent and timing of HA-MAL co-precipitation suggest MAL-containing vesicles are not the primary TGN-to-apical transport intermediates.","method":"Systematic transmembrane domain mutagenesis of HA; co-immunoprecipitation with MAL; domain-selective transport assays; detergent-resistant membrane fractionation; pulse-chase analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutagenesis combined with co-IP and transport assays, single lab","pmids":["14617347"],"is_preprint":false},{"year":2003,"finding":"MAL protein is expressed with a characteristic supranuclear granular distribution in multiple types of normal human epithelial cells throughout the respiratory, gastrointestinal, and genitourinary tracts and in exocrine/endocrine glands, consistent with MAL serving as a general component of the apical sorting machinery in diverse polarized human epithelia.","method":"Immunohistochemical survey using MAL-specific monoclonal antibody on normal and carcinoma human tissue sections","journal":"The journal of histochemistry and cytochemistry","confidence":"Low","confidence_rationale":"Tier 3 — immunolocalization only, no functional manipulation","pmids":["12704214"],"is_preprint":false},{"year":2004,"finding":"Genetic ablation of mal in mice results in cytoplasmic inclusions in compact myelin, everted paranodal loops, and disorganized transverse bands at the paranode-axon interface; MAL loss reduces protein levels of contactin-associated protein/paranodin, NF155, and Kv1.2 in myelin-derived rafts while nodal sodium channel clusters are unaltered, demonstrating a critical role for MAL in maintenance of CNS paranodal integrity, likely by controlling trafficking/sorting of NF155 and other membrane components in oligodendrocytes.","method":"Mal knockout mice; electron microscopy; immunofluorescence; subcellular fractionation of myelin and raft fractions; Western blot quantification of multiple myelin proteins","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic knockout with multiple structural and biochemical readouts, strong evidence","pmids":["15337780"],"is_preprint":false},{"year":2004,"finding":"MAL and Caveolin-1 co-fractionate with raft membranes and co-localize in a multivesicular intracellular compartment in PC-3 prostate cancer cells; MAL is present in prostasomes secreted by PC-3 cells, and prostasome secretion is reduced by wortmannin (PI3K inhibitor) but not brefeldin A, suggesting MAL-associated multivesicular compartments participate in PI3K-dependent prostasomal secretion rather than conventional secretory pathway.","method":"Subcellular fractionation; immunofluorescence co-localization; prostasome isolation from conditioned medium; electron microscopy; pharmacological inhibition (brefeldin A, wortmannin)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation with pharmacological dissection, single lab","pmids":["15466889"],"is_preprint":false},{"year":2004,"finding":"In metachromatic leukodystrophy (arylsulfatase A-deficient) mice, sulfatide accumulation in myelin causes a specific and severe reduction of MAL protein and mistargeting of MAL to the late endosomal/lysosomal compartment in renal epithelial cells, revealing a regulatory link between sulfatide levels and MAL expression/intracellular distribution.","method":"Arylsulfatase A-deficient mouse model; Western blot quantification of myelin proteins; immunofluorescence and subcellular fractionation in cultured renal epithelial cells with sulfatide loading","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model combined with cell culture mechanistic follow-up, single lab","pmids":["15193296"],"is_preprint":false},{"year":2009,"finding":"MAL forms oligomers via intramembrane protein-protein binding motifs and clusters sphingolipid raft markers while excluding phosphatidylethanolamine analogues; MAL-mediated raft lipid concentration is driven in part by positive hydrophobic mismatch between MAL transmembrane helices and membrane lipids; cholesterol and ceramide modulate MAL-raft association.","method":"Bimolecular fluorescence complementation (BiFC) for oligomerization; spontaneous clustering via DiHcRED-MAL fusion; antibody-mediated cross-linking of FLAG-MAL; site-directed mutagenesis of intramembrane motifs; exogenous cholesterol/ceramide membrane modulation; fluorescent lipid partitioning assays in COS7 cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis, BiFC, and lipid-manipulation experiments with multiple orthogonal readouts, single lab","pmids":["19553470"],"is_preprint":false},{"year":2010,"finding":"MAL interacts with Inverted Formin 2 (INF2) and requires INF2 for the formation of MAL-positive transport vesicles carrying Lck to the plasma membrane; MAL-positive vesicles move along microtubule tracks; INF2 knockdown reduces Lck at the plasma membrane and impairs immunological synapse formation; both actin polymerization and depolymerization activities of INF2 are required; Cdc42 and Rac1 regulate Lck transport in Jurkat and primary T cells.","method":"Co-immunoprecipitation of MAL with INF2; immunofluorescence co-localization; live videomicroscopy of MAL vesicle movement; siRNA knockdown of INF2; flow cytometry for surface Lck; immunological synapse assays; dominant-negative Cdc42/Rac1 constructs","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — co-IP, live imaging, loss-of-function, and rescue with multiple readouts, single lab","pmids":["20881207"],"is_preprint":false},{"year":2011,"finding":"MAL accumulates at the central supramolecular activation cluster (cSMAC) of the immunological synapse, where it co-localizes with condensed (raft) membranes; mislocalization of MAL to the peripheral SMAC reduces membrane condensation at the cSMAC and redistributes microtubule/vesicle docking machinery, causing Lck and LAT to be missorted to the pSMAC while TCR sorting is unaffected, demonstrating that MAL controls membrane order and protein sorting at the immunological synapse.","method":"Live-cell imaging of MAL-GFP during IS formation; Laurdan membrane order probe; MAL mistargeting constructs; immunofluorescence for SMAC components in Jurkat and primary T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — live imaging, membrane-order measurements, and gain-of-function mislocalization with defined cargo readouts, single lab","pmids":["21508261"],"is_preprint":false},{"year":2011,"finding":"MAL, but not its family member MAL2, self-associates and forms higher-order cholesterol-dependent complexes with apical cargo proteins, promoting formation of detergent-resistant membranes that recruit apical proteins; this biochemical activity is consistent with a role for MAL in raft coalescence and stabilization driven by hydrophobic mismatch between MAL's long transmembrane helices and short-acyl-chain Golgi phospholipids.","method":"Co-immunoprecipitation of MAL self-association; cholesterol depletion/replenishment; detergent-resistant membrane fractionation with apical cargo co-fractionation; comparison of MAL vs MAL2","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical co-fractionation with cholesterol manipulation and family-member comparison, single lab","pmids":["21732912"],"is_preprint":false},{"year":2016,"finding":"MAL is required for apical delivery of fusiform vesicles carrying uroplakins in urothelial umbrella cells; Rab27b functions upstream of MAL in the apical exocytic pathway, and MAL facilitates SNARE-mediated apical membrane fusion; keratin 20 defines a subapical compartment containing MAL-dependent fusion-primed vesicles.","method":"Immunomicroscopy of normal and Rab27b-knockout mouse urothelia; MAL-deficient mouse model; live imaging; genetic epistasis between Rab27b and MAL","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic models with epistasis analysis and multiple imaging approaches, single lab","pmids":["27009205"],"is_preprint":false},{"year":2019,"finding":"Clostridium perfringens epsilon toxin (ETX) binds to CNS microvasculature in a MAL-dependent manner; ETX-induced blood-brain barrier permeability via caveolae-dependent transcytosis requires expression of both MAL and caveolin-1; MAL-deficient mice show no detectable ETX binding to CNS vasculature and no BBB permeability, establishing MAL as a receptor or obligate co-factor for ETX binding on brain endothelial cells.","method":"In vivo ETX injection in wild-type, MAL-deficient, and caveolin-1-deficient mice; fluorescent tracer extravasation assays; immunofluorescence; electron microscopy of caveolae; endosomal marker analysis in primary brain endothelial cells","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple molecular and structural readouts, in vivo and in vitro, single lab","pmids":["31703116"],"is_preprint":false},{"year":2020,"finding":"MAL and PLP are exceptional among multipass transmembrane proteins in preferring ordered (raft) membrane domains; using giant plasma membrane vesicles (GPMVs), MAL showed high raft affinity among 24 multipass TMPs tested (92% had minimal raft affinity); PLP requires cholesterol and sphingolipids for raft association and appears to compete with MAL for cholesterol-mediated raft partitioning.","method":"Giant plasma membrane vesicle (GPMV) partitioning assay; systematic comparison of 24 multipass TMPs; cholesterol/sphingolipid depletion; competition assay between MAL and PLP","journal":"The journal of physical chemistry. B","confidence":"High","confidence_rationale":"Tier 1–2 — systematic quantitative assay with pharmacological dissection across a large protein panel, single lab","pmids":["32436385"],"is_preprint":false}],"current_model":"MAL (myelin and lymphocyte protein / VIP17 / MVP17) is a tetraspan proteolipid that constitutively associates with glycosphingolipid-cholesterol rafts via a C-terminal LIRW sorting motif and through hydrophobic mismatch-driven self-oligomerization; it cycles as an itinerant protein between the trans-Golgi network and the apical plasma membrane, where it clusters raft lipids, recruits apical cargo into detergent-resistant transport carriers, and facilitates SNARE-mediated apical membrane fusion—functions required for accurate apical sorting in polarized epithelia, paranodal maintenance in myelinating glia, Lck targeting to the immunological synapse in T cells, and serving as a surface receptor/co-factor for epsilon toxin binding on brain endothelial cells."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"prefetch_data":{"uniprot":{"accession":"P21145","full_name":"Myelin and lymphocyte protein","aliases":["T-lymphocyte maturation-associated protein"],"length_aa":153,"mass_kda":16.7,"function":"May be involved in vesicular trafficking from the Golgi apparatus to the cell membrane. Plays a role in the maintenance of the myelin sheath, and in axon-glia and glia-glia interactions","subcellular_location":"Membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P21145/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAL","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAL","total_profiled":1310},"omim":[{"mim_id":"620978","title":"LEUKODYSTROPHY, HYPOMYELINATING, 28; HLD28","url":"https://www.omim.org/entry/620978"},{"mim_id":"619222","title":"SUPPRESSOR OF CANCER CELL INVASION; SCAI","url":"https://www.omim.org/entry/619222"},{"mim_id":"617924","title":"EPILEPSY, JUVENILE MYOCLONIC, SUSCEPTIBILITY TO, 10; EJM10","url":"https://www.omim.org/entry/617924"},{"mim_id":"617831","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 55, WITH SEIZURES; MRD55","url":"https://www.omim.org/entry/617831"},{"mim_id":"616409","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 33; DEE33","url":"https://www.omim.org/entry/616409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":687.1},{"tissue":"esophagus","ntpm":2851.1},{"tissue":"vagina","ntpm":835.9}],"url":"https://www.proteinatlas.org/search/MAL"},"hgnc":{"alias_symbol":["MVP17","VIP17"],"prev_symbol":[]},"alphafold":{"accession":"P21145","domains":[{"cath_id":"1.20.58","chopping":"36-151","consensus_level":"high","plddt":94.0599,"start":36,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21145","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21145-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21145-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAL","jax_strain_url":"https://www.jax.org/strain/search?query=MAL"},"sequence":{"accession":"P21145","fasta_url":"https://rest.uniprot.org/uniprotkb/P21145.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21145/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21145"}},"corpus_meta":[{"pmid":"11544529","id":"PMC_11544529","title":"Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11544529","citation_count":938,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"5824068","id":"PMC_5824068","title":"Chromosome micromanipulation. 3. Spindle fiber tension and the reorientation of mal-oriented chromosomes.","date":"1969","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/5824068","citation_count":238,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10339572","id":"PMC_10339572","title":"VIP17/MAL, a lipid raft-associated protein, is involved in apical transport in MDCK cells.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10339572","citation_count":176,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11285253","id":"PMC_11285253","title":"Mutations in the gene encoding SLURP-1 in Mal de Meleda.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11285253","citation_count":170,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16439361","id":"PMC_16439361","title":"MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16439361","citation_count":165,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15239956","id":"PMC_15239956","title":"Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration.","date":"2004","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/15239956","citation_count":152,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10189374","id":"PMC_10189374","title":"The MAL proteolipid is necessary for normal apical transport and accurate sorting of the influenza virus hemagglutinin in Madin-Darby canine kidney cells.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10189374","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28759049","id":"PMC_28759049","title":"Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling.","date":"2017","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28759049","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25583269","id":"PMC_25583269","title":"Amygdala-prefrontal interactions in (mal)adaptive learning.","date":"2015","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/25583269","citation_count":141,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15610731","id":"PMC_15610731","title":"The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF.","date":"2004","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15610731","citation_count":136,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12072368","id":"PMC_12072368","title":"Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal?","date":"2002","source":"Trends in 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and duration of underlying cervical disease.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23456988","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8549777","id":"PMC_8549777","title":"VIP17/MAL, a proteolipid in apical transport vesicles.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8549777","citation_count":100,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19574958","id":"PMC_19574958","title":"Mal connects TLR2 to PI3Kinase activation and phagocyte polarization.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19574958","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10552968","id":"PMC_10552968","title":"The MAL gene is expressed in primary mediastinal large B-cell 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NF-κB, JNK, and ERK1/2. MAL can form homodimers and heterodimers with MyD88. A dominant-negative form of MAL specifically inhibits NF-κB activation by TLR4 or LPS but not by IL-1RI or IL-18R.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, NF-κB reporter assays, direct association studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional dominant-negative experiments, foundational paper with 938 citations replicated across field\",\n      \"pmids\": [\"11544529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAL undergoes tyrosine phosphorylation at residues Y86, Y106, and Y187 during TLR2 and TLR4 signaling. Bruton's tyrosine kinase (Btk) is the kinase responsible: Btk immunoprecipitated from LPS-stimulated THP-1 cells phosphorylates MAL in vitro, and a Btk inhibitor blocks endogenous MAL phosphorylation. Mutations at Y86 and Y187 act as dominant-negative inhibitors of NF-κB activation by LPS.\",\n      \"method\": \"In vitro kinase assay, Btk inhibitor treatment, site-directed mutagenesis, immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus mutagenesis plus pharmacological inhibition\",\n      \"pmids\": [\"16439361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IRAK1 and IRAK4 directly phosphorylate MAL (but not MyD88), leading to ubiquitination and proteasomal degradation of MAL following LPS stimulation of TLR4. Kinase-inactive forms of IRAK1/4 do not promote MAL degradation. This phosphorylation-dependent degradation serves as a negative regulatory mechanism for TLR2 and TLR4 signaling.\",\n      \"method\": \"In vitro kinase assay, IRAK1/4 knockdown, kinase-dead mutants, co-expression ubiquitination assay, IRAK1/4 inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay with kinase-dead controls plus RNAi knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"20400509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAL TIR domains spontaneously and reversibly form filaments in vitro and co-form filaments with TLR4 TIR domains, inducing MyD88 assembly. A 7-Å cryo-EM structure reveals a MAL protofilament of two parallel strands in a BB-loop-mediated head-to-tail arrangement. Structure-guided mutagenesis combined with in vivo interaction assays confirmed that MAL filament interface residues are required for TIR-domain interactions in both TLR and IL-1R signaling.\",\n      \"method\": \"Cryo-EM structure at 7 Å, site-directed mutagenesis, in vitro filament reconstitution, co-immunoprecipitation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus reconstitution plus mutagenesis with functional validation\",\n      \"pmids\": [\"28759049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the MAL/TIRAP TIR domain reveals a unique fold with a long loop replacing a β-strand present in other TIR domains, placing the BB-loop proline motif in a distinctive surface position. Site-directed mutagenesis of the proposed dimerization and MyD88-interacting interfaces confirmed key interface residues by co-immunoprecipitation.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional validation\",\n      \"pmids\": [\"21873236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMR solution structure of reduced MAL TIR domain shows structural rearrangement vs. disulfide-bonded crystal structure, including repositioning of the BB-loop. Cys91 has the highest redox potential of all cysteines in MAL and undergoes glutathionylation in LPS-stimulated macrophages. C91A mutation blocks MAL glutathionylation, acts as dominant negative, reduces MAL–MyD88 interaction, and diminishes MAL interaction with IRAK4 and MAL degradation.\",\n      \"method\": \"NMR structure determination, mass spectrometry (glutathionylation), site-directed mutagenesis, co-immunoprecipitation, redox NMR measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus mass spectrometry identification of PTM plus mutagenesis with functional assays\",\n      \"pmids\": [\"28739909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Upon TLR2/6 stimulation with diacylated lipoproteins, MAL directly interacts with the p85α regulatory subunit of PI3K in an inducible fashion, driving PI3K-dependent Akt phosphorylation, PIP3 generation, and macrophage polarization. This pathway is MyD88-independent for Akt phosphorylation. TLR2/1 does not require MAL or MyD88 for Akt phosphorylation, demonstrating specificity for TLR2/6.\",\n      \"method\": \"Co-immunoprecipitation, PI3K/Akt phosphorylation assays, MyD88-deficient cells, lipid measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple signaling readouts in genetic knockout backgrounds\",\n      \"pmids\": [\"19574958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAL mediates TLR2- and TLR4-dependent activation of CREB, leading to expression of IL-10 and COX-2. This pathway requires Pellino3, TRAF6, p38 MAPK, and its substrate MAPK-activated protein kinase 2 (MK2). MAL-deficient macrophages fail to activate CREB or express CREB-responsive genes in response to TLR2/4 ligands.\",\n      \"method\": \"MAL-deficient macrophages, Pellino3 knockdown, TRAF6-deficient cells, p38 inhibitor, kinase activity assays, gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined pathway placement via multiple genetic/pharmacological tools, single lab\",\n      \"pmids\": [\"21398611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein kinase Cδ (PKCδ) binds directly to the TIR domain of TIRAP/Mal. PKCδ depletion abolishes TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IκB in macrophages, placing PKCδ downstream of MAL in TLR signaling.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, PKCδ depletion, phosphorylation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — GST pulldown plus Co-IP plus functional depletion, single lab\",\n      \"pmids\": [\"17161867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAL has a TLR-independent role in IFN-γ receptor (IFNGR) signaling: MAL interacts with the IFNGR and mediates IFN-γ-induced p38 MAPK phosphorylation and autophagy. MAL-dependent IFNGR signaling is required for phagosome maturation and killing of intracellular M. tuberculosis. The S180L (human)/S200L (murine) variant reduces MAL affinity for the IFNGR, impairing IFN-γ signaling.\",\n      \"method\": \"Co-immunoprecipitation, MAL-deficient macrophages, autophagy assays, bacterial killing assays, surface plasmon resonance (affinity measurements)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic KO with defined functional readouts (bacterial killing, phagosome maturation), affinity measurements for polymorphic variant\",\n      \"pmids\": [\"26885859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"VIP17/MAL is a tetraspan proteolipid that associates with sphingolipid-cholesterol lipid rafts in MDCK cells and localizes to post-Golgi transport containers and the apical cell surface. Overexpression of MAL increases apical delivery; antisense RNA depletion causes Golgi accumulation and impaired apical transport of influenza hemagglutinin, clusterin, gp114, and GPI-anchored proteins, but not basolateral E-cadherin. This demonstrates MAL is part of the machinery for raft-mediated apical transport.\",\n      \"method\": \"Antisense RNA depletion, overexpression, immunofluorescence microscopy, subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with multiple apical cargo readouts, replicated with rescue experiment\",\n      \"pmids\": [\"10339572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAL depletion by antisense oligonucleotides in MDCK cells diminishes the presence of influenza hemagglutinin (HA) in glycolipid-enriched membranes (GEMs), reduces the rate of HA transport to the cell surface, inhibits apical delivery of HA, and causes partial missorting to the basolateral membrane. Ectopic MAL expression in MAL-depleted cells rescues these defects.\",\n      \"method\": \"Antisense oligonucleotide depletion, surface biotinylation, pulse-chase transport assays, sucrose gradient fractionation, rescue by ectopic MAL expression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — loss-of-function with multiple orthogonal readouts plus specific rescue, foundational paper\",\n      \"pmids\": [\"10189374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAL is an itinerant protein that cycles between the trans-Golgi network (TGN) and the plasma membrane. MAL is expressed on the cell surface, rapidly internalized, and approximately 30% of internalized MAL is delivered back to the TGN. Retrieval requires endosomal acidification (blocked by chloroquine, monensin, NH4Cl). This itinerant behavior is consistent with its role as an integral machinery component for apical transport.\",\n      \"method\": \"Surface biotinylation, anti-FLAG antibody binding assays, neuraminidase sensitivity/resialylation, drug treatments, immunofluorescence, flow cytometry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal localization and trafficking assays with pharmacological perturbations\",\n      \"pmids\": [\"10512878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MAL associates with glycolipid-enriched membrane (GEM) microdomains in T lymphocytes and co-immunoprecipitates with GPI-anchored proteins (CD59) and Src-family kinases (Lck) in both plasma membrane and endosomal-enriched membrane fractions.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, sucrose gradient, monoclonal antibody generation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP association study, single lab, no functional follow-up in this paper\",\n      \"pmids\": [\"9842910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A C-terminal juxtamembrane tetrapeptide motif LIRW in MAL is required for incorporation into GEM (glycolipid-enriched membrane) microdomains. The arginine within LIRW is the most critical residue; mutagenesis shows that loss of GEM incorporation correlates with loss of brefeldin A sensitivity, suggesting GEM-localization is required for MAL's function in the Golgi secretory pathway.\",\n      \"method\": \"Site-directed mutagenesis, sucrose gradient fractionation, pulse-chase experiments, brefeldin A treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis identifying sorting motif with functional readouts\",\n      \"pmids\": [\"9582298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Genetic ablation of the mal gene in mice results in cytoplasmic inclusions in compact myelin, everted paranodal loops, disorganized transverse bands at the paranode-axon interface, and marked reduction of contactin-associated protein/paranodin, NF155, and Kv1.2 channel at paranodes in the CNS. Biochemical analysis showed reduced MAG, MBP, and NF155 in myelin-derived rafts, demonstrating MAL is required for maintenance of CNS paranodal structure, likely by controlling trafficking/sorting of NF155 and other membrane components in oligodendrocytes.\",\n      \"method\": \"MAL knockout mouse, electron microscopy, immunofluorescence, biochemical fractionation, protein level analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined ultrastructural and molecular phenotypes, multiple readouts\",\n      \"pmids\": [\"15337780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAL interacts with Inverted Formin 2 (INF2) in Jurkat T cells; MAL(+) vesicles transporting Lck to the plasma membrane move along microtubule tracks. INF2 knockdown greatly reduces MAL(+) transport vesicle formation and Lck plasma membrane levels, impairing immunological synapse formation. Both actin polymerization and depolymerization activities of INF2 are required. Cdc42 and Rac1, which bind INF2, regulate Lck transport.\",\n      \"method\": \"Co-immunoprecipitation, videomicroscopy, siRNA knockdown, immunological synapse assay, surface Lck quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus live-cell imaging plus functional knockdown with specific readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"20881207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAL accumulates at the central SMAC (cSMAC) at the immunological synapse in Jurkat T cells and primary T cells, where it colocalizes with condensed (raft) membranes. Mislocalization of MAL to the peripheral SMAC (pSMAC) reduces membrane condensation at the cSMAC and redistributes microtubule/transport vesicle docking machinery, causing missorting of Lck and LAT (but not TCR) to the pSMAC.\",\n      \"method\": \"Live-cell fluorescence microscopy, Laurdan membrane order probe, MAL mislocalization constructs, immunological synapse formation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments tied to functional consequence (protein missorting), multiple readouts\",\n      \"pmids\": [\"21508261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAL forms oligomers via intramembrane protein-protein interactions identified by bimolecular fluorescence complementation (BiFC) analysis. MAL clusters laterally concentrate sphingolipid raft markers and exclude phosphatidylethanolamine. Hydrophobic mismatch between MAL transmembrane helices and membrane lipids drives raft association. Site-directed mutagenesis of intramembrane binding motifs disrupts oligomerization.\",\n      \"method\": \"BiFC analysis, antibody-mediated cross-linking, site-directed mutagenesis, exogenous lipid modulation, confocal microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution/BiFC plus mutagenesis plus lipid manipulation, multiple orthogonal methods\",\n      \"pmids\": [\"19553470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAL/MRTF-A (acting as SRF coactivator) is recruited to the mig6/errfi-1 promoter in response to actin dynamics changes. MAL-mediated mig6 induction negatively regulates EGFR and MAPK/Erk signaling. Depletion of Mig6 restores EGFR signaling; MAL overexpression has antiproliferative effects requiring SRF-binding and transactivation domains.\",\n      \"method\": \"Chromatin immunoprecipitation, gene expression profiling, siRNA knockdown, promoter reporter assays, actin-binding drug treatments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assays plus functional knockdown/overexpression, multiple orthogonal methods\",\n      \"pmids\": [\"19683494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A seven-residue sequence in the MAL B1 region (with the adjacent Q-box) is necessary and sufficient for interaction with the SRF DNA-binding domain. MAL interacts with SRF via a hydrophobic groove/pocket, contacts DNA flanking the SRF-protected region directly, and forms a β-strand addition to the SRF DNA-binding domain β-sheet. SRF DNA bending facilitates MAL-DNA contact and complex formation.\",\n      \"method\": \"Deletion/mutation analysis, gel mobility shift assays, DNase I footprinting, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic mutagenesis plus DNase I footprinting plus EMSA defining binding interface\",\n      \"pmids\": [\"16705166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAL/MRTF-A (MAL-D in Drosophila) nuclear accumulation is induced by cell stretching/tension during border cell migration in Drosophila. Border cells lacking ability to migrate lack nuclear MAL-D but can accumulate it if pulled by other migrating cells. MAL-D responds to activated Diaphanous (affecting actin dynamics). MAL-D/SRF activity is required to build a robust actin cytoskeleton; mutant cells break apart upon initiating migration.\",\n      \"method\": \"Drosophila genetics, live-cell imaging, dominant-active Diaphanous expression, loss-of-function analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Drosophila ortholog genetic analysis, direct observation of tension-induced nuclear translocation with functional consequence, multiple genetic approaches\",\n      \"pmids\": [\"15239956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Genetic evidence in both Drosophila and human cell models demonstrates that actin (specifically actin gene targets) is the key MAL/SRF target required for invasive cell migration. Actin protein feeds back on actin mRNA production via MAL/SRF, constituting a dedicated homeostatic feedback system for actin levels.\",\n      \"method\": \"Genetic epistasis in Drosophila, human cell models, rescue experiments, loss-of-function\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis across two organisms with defined mechanistic pathway\",\n      \"pmids\": [\"24831700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAL/SRF complex directly regulates MYL9 (MLC2) and MMP9 promoters in megakaryocytes, as demonstrated by luciferase assays and chromatin immunoprecipitation in primary megakaryocytes. MAL knockdown reduces filopodia/lamellipodia formation, stress fiber assembly, proplatelet formation, and megakaryocyte migration (via MMP9). MAL nuclear localization occurs after Rho GTPase activation by adhesion to collagen I.\",\n      \"method\": \"siRNA knockdown, ChIP, luciferase reporter assays, live-cell microscopy, megakaryocyte differentiation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays plus functional KD with defined cellular phenotypes\",\n      \"pmids\": [\"19724058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The GEF Bcr activates RhoA upstream of MAL/SRF signaling in keratinocytes. Loss of Bcr reduces RhoA activity, stress fibers, focal adhesions, and MAL/SRF-dependent gene expression including desmoglein-1 (Dsg1), keratin-1, and loricrin. Ectopic Dsg1 rescues differentiation defects seen upon loss of Bcr or MAL, placing Dsg1 downstream of Bcr-RhoA-MAL-SRF.\",\n      \"method\": \"siRNA knockdown, RhoA activity assays, gene expression analysis, rescue experiments, epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by rescue experiment plus functional knockdown with defined differentiation readouts\",\n      \"pmids\": [\"23940119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FHL2 physically interacts with SRF and competes with MAL/MRTF-A for SRF binding to selectively antagonize induction of smooth muscle (SM) target genes but not immediate-early genes (IEGs) or cardiac genes. FHL2 is itself a RhoA/MAL-regulated SRF target gene, constituting an autoregulatory feedback mechanism.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, expression profiling, competition binding\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP plus functional reporter assays demonstrating competition mechanism\",\n      \"pmids\": [\"15610731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Disassembly of E-cadherin-dependent epithelial cell-cell junctions activates SRF-mediated transcription through monomeric actin and MAL. This signaling requires Rac1 (not RhoA) and actomyosin contractility, in contrast to serum-stimulated fibroblasts where RhoA is required. E-cadherin-null cells show no SRF activation.\",\n      \"method\": \"Clostridial cytotoxin treatment, Ca2+ chelation, siRNA knockdown, E-cadherin-null cells, SRF reporter assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic/pharmacological dissection of pathway with specific readout; multiple tools\",\n      \"pmids\": [\"18334560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAL expression on the apical surface of brain endothelial cells is required for Clostridium perfringens epsilon toxin (ETX) binding to CNS microvasculature. ETX-induced blood-brain barrier permeability requires both MAL and caveolin-1 expression and occurs via caveolae-dependent transcytosis: ETX binding to MAL recruits caveolin-1, triggers caveolae formation and internalization, followed by trafficking through early to late endosomes/multivesicular bodies.\",\n      \"method\": \"MAL-deficient and caveolin-1-deficient mice, in vivo BBB permeability assays, electron microscopy, endosomal marker analysis, fluorescent tracer extravasation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mice with in vivo functional readout plus ultrastructural analysis, mechanistic pathway established\",\n      \"pmids\": [\"31703116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In urothelial umbrella cells, MAL facilitates apical fusion of uroplakin-carrying fusiform vesicles (FVs) after Rab8/11- and Rab27b-mediated apical transport along actin filaments and SNARE-mediated membrane anchorage. Rab27b works upstream of MAL in this sequential pathway. Rab27b knockout leads to uroplakin and Slp2-a destabilization.\",\n      \"method\": \"Immunomicroscopy of normal and Rab27b-knockout mouse urothelia, genetic epistasis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — genetic epistasis in mouse model with defined pathway order, single lab\",\n      \"pmids\": [\"27009205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAL (MRTF-A/MKL1) expression in neurons is localized to cell bodies and apical dendrites. Expression of dominant-negative MAL constructs or MAL siRNA in cultured cortical neurons reduces the number of dendritic processes and decreases basal SRF-mediated transcription, demonstrating that the MAL-SRF pathway regulates dendritic morphology.\",\n      \"method\": \"Immunohistochemistry, siRNA knockdown, dominant-negative constructs, SRF reporter assays, morphometric analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — siRNA and dominant-negative with defined morphological readout, single lab\",\n      \"pmids\": [\"16945101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAL (but not MAL2) self-associates and forms higher-order, cholesterol-dependent complexes with apical proteins in hepatic WIF-B cells, promoting formation of detergent-resistant membranes that recruit apical cargo. This raft coalescence is driven by hydrophobic mismatch between MAL's long transmembrane helices and short-acyl-chain Golgi phospholipids.\",\n      \"method\": \"Biochemical fractionation, sucrose gradient, co-immunoprecipitation, cholesterol depletion, detergent-resistance assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — biochemical reconstitution-like experiments with lipid modulation, single lab\",\n      \"pmids\": [\"21732912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mal is engaged in TLR9-dependent expression of IFNβ and TNFα in HSV-1-infected or CpG-C-treated macrophages, requiring a noncanonical NF-κB pathway. ERK1/2 kinases are involved in TLR9-dependent IFNβ and TNFα induction, and loss of Mal specifically impairs ERK1/2-mediated induction of noncanonical NF-κB and concomitant cytokine production.\",\n      \"method\": \"MAL-deficient macrophages, ERK1/2 inhibitor treatment, NF-κB pathway analysis, cytokine measurement\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined signaling pathway readouts, single lab, novel role\",\n      \"pmids\": [\"31851971\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAL (TIRAP/MyD88-adapter-like) is a multifunctional protein with two major mechanistic roles: (1) as a TIR-domain-containing adapter that bridges TLR2 and TLR4 to MyD88 and IRAK kinases via BB-loop-mediated TIR-domain filamentous assemblies—undergoing Btk-mediated tyrosine phosphorylation, IRAK1/4-mediated serine phosphorylation, Cys91 glutathionylation, and subsequent ubiquitination/degradation as regulatory steps, while also connecting TLR2/6 to PI3K/Akt and TLR9 to noncanonical NF-κB, and mediating IFN-γ receptor signaling for phagosome maturation; and (2) as the myelin and lymphocyte protein (MAL/VIP17), a tetraspan proteolipid that localizes to glycolipid-enriched raft membranes via a C-terminal LIRW motif, oligomerizes to cluster and stabilize raft domains, and cycles between the TGN and apical plasma membrane as an essential component of the machinery for raft-dependent apical protein sorting in polarized epithelial cells, oligodendrocytes, and T lymphocytes—where it additionally facilitates MAL/MRTF-A-dependent SRF transcriptional coactivation in response to Rho-actin signaling to regulate cytoskeletal gene expression, dendritic morphology, megakaryocyte differentiation, and invasive cell migration.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify papers before extracting discoveries.\n\n**Classification notes:**\n- MAL (myelin and lymphocyte protein / VIP17 / MVP17): tetraspan proteolipid involved in apical transport and lipid raft organization in epithelial/myelin cells — KEEP\n- MAL (MyD88-adapter-like / TIRAP): TLR adaptor protein — KEEP (same gene symbol, different protein — actually this IS a different gene: TIRAP/MAL. But the corpus treats both. I'll track carefully)\n- MAL/MKL1 (Megakaryoblastic Leukemia 1 / MRTF-A): transcriptional coactivator for SRF — KEEP (this is MKL1, not the MAL proteolipid. Different gene. EXCLUDE as alias collision)\n- Mal d 1: apple allergen — EXCLUDE (plant gene, symbol collision)\n- MAL loci in Saccharomyces: maltose utilization — EXCLUDE (yeast metabolic genes, symbol collision)\n- MAL-PDT (methyl aminolevulinate): photodynamic therapy drug — EXCLUDE\n- MAL-ED study: Malnutrition and Enteric Disease study — EXCLUDE\n- \"mal\" used as prefix for \"maladaptive\" — EXCLUDE\n\nLet me re-examine the two main human MAL proteins:\n1. **MAL proteolipid** (gene: MAL, chr 2q13): tetraspan membrane protein in T cells, myelin, epithelial apical transport — KEEP\n2. **MAL/TIRAP** (gene: TIRAP, chr 11q24): TLR adaptor — this is actually encoded by *TIRAP* gene, but called \"Mal\" in literature. The query gene \"MAL\" — I need to determine which is the canonical MAL gene being queried. Given that the gene symbol MAL maps to the proteolipid (HGNC:6817), TIRAP papers are alias collision. However, the corpus heavily features TIRAP papers under \"Mal.\" I'll KEEP TIRAP papers since \"Mal\" is an established alias used in the literature for TIRAP/MAL, and the query may encompass both — but actually HGNC \"MAL\" is the proteolipid. TIRAP is a separate gene. I'll EXCLUDE TIRAP papers as alias collision.\n3. **MKL1/MAL/MRTF-A**: This is MKL1 gene, called MAL in some papers (megakaryoblastic acute leukemia). EXCLUDE as alias collision.\n\n**Final classification:**\n\nKEEP (MAL proteolipid): [3], [7], [13], [14], [18], [20], [29], [31], [33], [41], [46], [48], [55], [60], [62], [76], [91], [92], [94], [95], [98], [99]\n\nKEEP (with functional mechanistic data on MAL proteolipid from additional papers): [81]\n\nEXCLUDE - TIRAP/Mal (different gene): [1], [5], [8], [11], [15], [19], [37], [45], [50], [54], [71], [80], [82], [84], [88]\nEXCLUDE - MKL1/MRTF-A (different gene called MAL): [6], [10], [22], [27], [28], [34], [68], [72], [73]\nEXCLUDE - Saccharomyces MAL loci: [12], [32], [35], [38], [89], [96], [97]\nEXCLUDE - Mal d 1 (apple allergen): [36], [39], [40], [66], [79], [85], [86]\nEXCLUDE - MAL-PDT: [30], [67]\nEXCLUDE - MAL-ED study: [43], [75]\nEXCLUDE - Methylation biomarker studies (no mechanism): [17], [23], [25], [51], [52], [56], [59], [63], [64], [69], [74], [83], [90]\nEXCLUDE - \"mal\" as prefix/other: [2], [4], [9], [16], [24], [44], [47], [49], [53], [57], [58], [61], [65], [70], [77], [78], [87], [93], [100]\n\nWait — [49] \"Protease activation in apoptosis induced by MAL\" — this MAL is \"HAMLET-like\" (folding variant of alpha-lactalbumin), not MAL proteolipid. EXCLUDE.\n[4] Mal de Meleda / SLURP-1 — EXCLUDE (different gene).\n[20] MAL gene expressed in lymphoma — mentions MAL proteolipid in GEM domains. KEEP for localization data.\n[13] MVP17 cloning — KEEP (MAL proteolipid ortholog in oligodendrocytes).\n\nFor additional curated papers:\n- [23] MKL1/MRTF-A SRF coactivator papers — EXCLUDE\n- [24] RBM15-MKL1 fusion — EXCLUDE  \n- [28] MAL gene in t(1;22) — this refers to MKL1/MAL — EXCLUDE\n- [11] Myocardin/SRF — EXCLUDE\n- [19] MRTF-A/B — EXCLUDE\n- [20] MRTF metastasis — EXCLUDE\n- [25] MRTF EMT — EXCLUDE\n- [26] MRTF metastasis — EXCLUDE\n- [30] BMP/MRTF — EXCLUDE\n- Rest are phosphoproteomics/interactome/genomics — not mechanistic for MAL proteolipid\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"VIP17/MAL (canine homolog of human MAL proteolipid) localizes to apical transport vesicles in MDCK cells, cycling between the Golgi complex and the apical plasma membrane, consistent with a role as a component of the vesicular trafficking machinery for apical sorting.\",\n      \"method\": \"Immunofluorescence microscopy of epitope-tagged VIP17/MAL in BHK and MDCK cells; subcellular fractionation; biochemical enrichment in CHAPS-insoluble complexes\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with subcellular fractionation, single lab\",\n      \"pmids\": [\"8549777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"MVP17, the rat oligodendrocyte homolog of human MAL (88.9% identity), is expressed specifically in oligodendrocytes and brain during active myelination and is enriched in detergent-insoluble protein-lipid complexes, indicating association with glycolipid-rich microdomains during myelinogenesis.\",\n      \"method\": \"Protein microsequencing, cDNA cloning, Northern analysis, in vitro translation, two-dimensional gel electrophoresis of detergent-insoluble fractions\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation plus molecular cloning, single lab\",\n      \"pmids\": [\"8583510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MAL and caveolin occupy distinct lipid microenvironments within internal detergent-insoluble membranes of MDCK cells; MAL resides in an internal glycolipid-enriched microdomain independently of caveolin expression, demonstrating heterogeneity within the raft compartment.\",\n      \"method\": \"Sucrose-gradient fractionation of Triton X-100 cell extracts; immunofluorescence in MDCK, Jurkat, and A498 cells; detergent-solubilization assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal biochemical and imaging methods, single lab\",\n      \"pmids\": [\"9168919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MAL is identified as a member of an extended gene family that includes plasmolipin, BENE, and other tetraspan proteins; the conserved fingerprint motif -[Q/Y-G-W-V-M-F/Y-V]- at the first extracellular loop/second transmembrane domain junction defines the MAL protein family.\",\n      \"method\": \"Mouse MAL cDNA cloning and structural gene characterization; database searches and computer-aided sequence analysis; Northern blot expression analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with sequence-based family definition, single lab\",\n      \"pmids\": [\"9168137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MAL associates with GPI-anchored proteins and Src-like tyrosine kinases (including Lck) in glycolipid-enriched membrane (GEM) microdomains of T lymphocytes; co-immunoprecipitation with anti-MAL and anti-CD59 antibodies demonstrated specific association in both cell lines and primary T cells, and MAL and Lck co-localize in endosomal GEM fractions.\",\n      \"method\": \"Monoclonal antibody generation against MAL; co-immunoprecipitation; sucrose-gradient fractionation of GEM microdomains from HPB-ALL and primary human T lymphocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal co-IP in two cell types, single lab\",\n      \"pmids\": [\"9842910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A C-terminal tetrapeptide motif LIRW is necessary for incorporation of MAL into glycolipid-enriched membrane (GEM) microdomains; the arginine within LIRW is the most critical residue, and loss of GEM incorporation correlates with loss of brefeldin A sensitivity, linking GEM association to Golgi-dependent transport function.\",\n      \"method\": \"Site-directed mutagenesis of MAL C-terminus; pulse-chase experiments; sucrose-gradient fractionation of GEM fractions; brefeldin A treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined sorting motif and functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9582298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAL is necessary for both normal apical transport rate and accurate sorting of influenza virus hemagglutinin (HA) to the apical surface of MDCK cells; MAL depletion reduces HA association with GEMs, slows surface delivery, inhibits apical delivery, and causes partial basolateral missorting; these defects are rescued by ectopic MAL re-expression.\",\n      \"method\": \"Antisense oligonucleotide-based MAL depletion; ectopic MAL expression rescue; surface biotinylation; domain-specific transport assays; monoclonal antibody to canine MAL\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with rescue, multiple cargo readouts, single lab\",\n      \"pmids\": [\"10189374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of VIP17/MAL in MDCK cells increases apical delivery and expands the apical surface domain; antisense-mediated knockdown causes Golgi accumulation and impaired apical transport of multiple apical markers (HA, clusterin/gp80, gp114, GPI-anchored protein) without affecting basolateral E-cadherin distribution, establishing MAL as a component of the apical sorting machinery that operates via sphingolipid-cholesterol rafts.\",\n      \"method\": \"Stable over-expression and antisense RNA expression in MDCK cells; immunofluorescence; domain-selective transport assays for multiple cargo proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (OE and KD) with multiple cargo readouts, replicated across cargo types\",\n      \"pmids\": [\"10339572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAL is an itinerant protein that cycles between the trans-Golgi network (TGN) and the plasma membrane; surface-expressed MAL is rapidly internalized via an endosomal pathway requiring endosomal acidification, and approximately 30% of internalized MAL is recycled back to the TGN, consistent with a role as a reusable component of the apical transport machinery.\",\n      \"method\": \"FLAG-epitope and O-glycosylation tag insertion into MAL extracellular loop; surface biotinylation; anti-FLAG surface binding; neuraminidase sensitivity; resialylation assays; flow cytometry; chloroquine/monensin/NH4Cl inhibition\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal approaches (biotinylation, glycan chemistry, pharmacological inhibition) establishing itinerant trafficking cycle, single lab\",\n      \"pmids\": [\"10512878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAL co-purifies with specific glycosphingolipids (galactosylceramide and sulfatide) in detergent-insoluble domains in myelin and epithelial cells, indicating a close functional association with glycosphingolipid-enriched microdomains; MAL is localized to compact myelin in the nervous system and to the apical plasma membrane in kidney and stomach epithelial cells.\",\n      \"method\": \"Biochemical co-purification with detergent-resistant membranes; immunolocalization in multiple tissues\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — biochemical co-fractionation and immunolocalization, review synthesizing multiple studies\",\n      \"pmids\": [\"10739088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Features required for HA apical sorting in MDCK cells differ from those required for DRM association or MAL co-precipitation; mutations in HA transmembrane residues that prevent DRM association also decrease MAL co-precipitation, but DRM association is not sufficient for apical sorting; the limited extent and timing of HA-MAL co-precipitation suggest MAL-containing vesicles are not the primary TGN-to-apical transport intermediates.\",\n      \"method\": \"Systematic transmembrane domain mutagenesis of HA; co-immunoprecipitation with MAL; domain-selective transport assays; detergent-resistant membrane fractionation; pulse-chase analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis combined with co-IP and transport assays, single lab\",\n      \"pmids\": [\"14617347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MAL protein is expressed with a characteristic supranuclear granular distribution in multiple types of normal human epithelial cells throughout the respiratory, gastrointestinal, and genitourinary tracts and in exocrine/endocrine glands, consistent with MAL serving as a general component of the apical sorting machinery in diverse polarized human epithelia.\",\n      \"method\": \"Immunohistochemical survey using MAL-specific monoclonal antibody on normal and carcinoma human tissue sections\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — immunolocalization only, no functional manipulation\",\n      \"pmids\": [\"12704214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Genetic ablation of mal in mice results in cytoplasmic inclusions in compact myelin, everted paranodal loops, and disorganized transverse bands at the paranode-axon interface; MAL loss reduces protein levels of contactin-associated protein/paranodin, NF155, and Kv1.2 in myelin-derived rafts while nodal sodium channel clusters are unaltered, demonstrating a critical role for MAL in maintenance of CNS paranodal integrity, likely by controlling trafficking/sorting of NF155 and other membrane components in oligodendrocytes.\",\n      \"method\": \"Mal knockout mice; electron microscopy; immunofluorescence; subcellular fractionation of myelin and raft fractions; Western blot quantification of multiple myelin proteins\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic knockout with multiple structural and biochemical readouts, strong evidence\",\n      \"pmids\": [\"15337780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAL and Caveolin-1 co-fractionate with raft membranes and co-localize in a multivesicular intracellular compartment in PC-3 prostate cancer cells; MAL is present in prostasomes secreted by PC-3 cells, and prostasome secretion is reduced by wortmannin (PI3K inhibitor) but not brefeldin A, suggesting MAL-associated multivesicular compartments participate in PI3K-dependent prostasomal secretion rather than conventional secretory pathway.\",\n      \"method\": \"Subcellular fractionation; immunofluorescence co-localization; prostasome isolation from conditioned medium; electron microscopy; pharmacological inhibition (brefeldin A, wortmannin)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation with pharmacological dissection, single lab\",\n      \"pmids\": [\"15466889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In metachromatic leukodystrophy (arylsulfatase A-deficient) mice, sulfatide accumulation in myelin causes a specific and severe reduction of MAL protein and mistargeting of MAL to the late endosomal/lysosomal compartment in renal epithelial cells, revealing a regulatory link between sulfatide levels and MAL expression/intracellular distribution.\",\n      \"method\": \"Arylsulfatase A-deficient mouse model; Western blot quantification of myelin proteins; immunofluorescence and subcellular fractionation in cultured renal epithelial cells with sulfatide loading\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model combined with cell culture mechanistic follow-up, single lab\",\n      \"pmids\": [\"15193296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAL forms oligomers via intramembrane protein-protein binding motifs and clusters sphingolipid raft markers while excluding phosphatidylethanolamine analogues; MAL-mediated raft lipid concentration is driven in part by positive hydrophobic mismatch between MAL transmembrane helices and membrane lipids; cholesterol and ceramide modulate MAL-raft association.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) for oligomerization; spontaneous clustering via DiHcRED-MAL fusion; antibody-mediated cross-linking of FLAG-MAL; site-directed mutagenesis of intramembrane motifs; exogenous cholesterol/ceramide membrane modulation; fluorescent lipid partitioning assays in COS7 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis, BiFC, and lipid-manipulation experiments with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"19553470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAL interacts with Inverted Formin 2 (INF2) and requires INF2 for the formation of MAL-positive transport vesicles carrying Lck to the plasma membrane; MAL-positive vesicles move along microtubule tracks; INF2 knockdown reduces Lck at the plasma membrane and impairs immunological synapse formation; both actin polymerization and depolymerization activities of INF2 are required; Cdc42 and Rac1 regulate Lck transport in Jurkat and primary T cells.\",\n      \"method\": \"Co-immunoprecipitation of MAL with INF2; immunofluorescence co-localization; live videomicroscopy of MAL vesicle movement; siRNA knockdown of INF2; flow cytometry for surface Lck; immunological synapse assays; dominant-negative Cdc42/Rac1 constructs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, live imaging, loss-of-function, and rescue with multiple readouts, single lab\",\n      \"pmids\": [\"20881207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAL accumulates at the central supramolecular activation cluster (cSMAC) of the immunological synapse, where it co-localizes with condensed (raft) membranes; mislocalization of MAL to the peripheral SMAC reduces membrane condensation at the cSMAC and redistributes microtubule/vesicle docking machinery, causing Lck and LAT to be missorted to the pSMAC while TCR sorting is unaffected, demonstrating that MAL controls membrane order and protein sorting at the immunological synapse.\",\n      \"method\": \"Live-cell imaging of MAL-GFP during IS formation; Laurdan membrane order probe; MAL mistargeting constructs; immunofluorescence for SMAC components in Jurkat and primary T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging, membrane-order measurements, and gain-of-function mislocalization with defined cargo readouts, single lab\",\n      \"pmids\": [\"21508261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAL, but not its family member MAL2, self-associates and forms higher-order cholesterol-dependent complexes with apical cargo proteins, promoting formation of detergent-resistant membranes that recruit apical proteins; this biochemical activity is consistent with a role for MAL in raft coalescence and stabilization driven by hydrophobic mismatch between MAL's long transmembrane helices and short-acyl-chain Golgi phospholipids.\",\n      \"method\": \"Co-immunoprecipitation of MAL self-association; cholesterol depletion/replenishment; detergent-resistant membrane fractionation with apical cargo co-fractionation; comparison of MAL vs MAL2\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical co-fractionation with cholesterol manipulation and family-member comparison, single lab\",\n      \"pmids\": [\"21732912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAL is required for apical delivery of fusiform vesicles carrying uroplakins in urothelial umbrella cells; Rab27b functions upstream of MAL in the apical exocytic pathway, and MAL facilitates SNARE-mediated apical membrane fusion; keratin 20 defines a subapical compartment containing MAL-dependent fusion-primed vesicles.\",\n      \"method\": \"Immunomicroscopy of normal and Rab27b-knockout mouse urothelia; MAL-deficient mouse model; live imaging; genetic epistasis between Rab27b and MAL\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic models with epistasis analysis and multiple imaging approaches, single lab\",\n      \"pmids\": [\"27009205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Clostridium perfringens epsilon toxin (ETX) binds to CNS microvasculature in a MAL-dependent manner; ETX-induced blood-brain barrier permeability via caveolae-dependent transcytosis requires expression of both MAL and caveolin-1; MAL-deficient mice show no detectable ETX binding to CNS vasculature and no BBB permeability, establishing MAL as a receptor or obligate co-factor for ETX binding on brain endothelial cells.\",\n      \"method\": \"In vivo ETX injection in wild-type, MAL-deficient, and caveolin-1-deficient mice; fluorescent tracer extravasation assays; immunofluorescence; electron microscopy of caveolae; endosomal marker analysis in primary brain endothelial cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple molecular and structural readouts, in vivo and in vitro, single lab\",\n      \"pmids\": [\"31703116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAL and PLP are exceptional among multipass transmembrane proteins in preferring ordered (raft) membrane domains; using giant plasma membrane vesicles (GPMVs), MAL showed high raft affinity among 24 multipass TMPs tested (92% had minimal raft affinity); PLP requires cholesterol and sphingolipids for raft association and appears to compete with MAL for cholesterol-mediated raft partitioning.\",\n      \"method\": \"Giant plasma membrane vesicle (GPMV) partitioning assay; systematic comparison of 24 multipass TMPs; cholesterol/sphingolipid depletion; competition assay between MAL and PLP\",\n      \"journal\": \"The journal of physical chemistry. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic quantitative assay with pharmacological dissection across a large protein panel, single lab\",\n      \"pmids\": [\"32436385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAL (myelin and lymphocyte protein / VIP17 / MVP17) is a tetraspan proteolipid that constitutively associates with glycosphingolipid-cholesterol rafts via a C-terminal LIRW sorting motif and through hydrophobic mismatch-driven self-oligomerization; it cycles as an itinerant protein between the trans-Golgi network and the apical plasma membrane, where it clusters raft lipids, recruits apical cargo into detergent-resistant transport carriers, and facilitates SNARE-mediated apical membrane fusion—functions required for accurate apical sorting in polarized epithelia, paranodal maintenance in myelinating glia, Lck targeting to the immunological synapse in T cells, and serving as a surface receptor/co-factor for epsilon toxin binding on brain endothelial cells.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n"}