{"gene":"HSPA1L","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"Hsp70-Hom (HSPA1L) binds peptides (peptide binding specificity characterized for the first time), is expressed endogenously in human cell lines, localizes to the cytoplasm under basal conditions and concentrates in the nucleus after heat shock, and is specifically upregulated at the protein level by interferon-gamma and at the mRNA level by LPS treatment.","method":"Peptide binding assay, immunolocalization/subcellular fractionation, RNA expression profiling in human tissues and cell lines, western blot","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding assay, localization, expression) in a single characterization study; not independently replicated","pmids":["11599570"],"is_preprint":false},{"year":2004,"finding":"A nonsynonymous polymorphism in HSPA1L (M493T substitution in the peptide-binding subunit) co-occurs with HLA-B*5701 and is necessary for abacavir hypersensitivity, implicating the peptide-binding domain of HSPA1L in antigen presentation or immune modulation.","method":"Fine recombinant genetic mapping, haplotype analysis, ex vivo abacavir stimulation with CD8+ T cell depletion and monocyte TNF measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping with functional ex vivo assay (CD8 depletion experiment), single study with multiple methods","pmids":["15024131"],"is_preprint":false},{"year":2014,"finding":"Six rare HSPA1L variant proteins (p.Ser277Leu, p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) all showed decreased chaperone activity in vitro compared to wild-type HSPA1L, and three of the variants demonstrated dominant negative effects on both HSPA1L and HSPA1A chaperone activity.","method":"In vitro chaperone activity biochemical assay of variant proteins; dominant-negative assessment","journal":"Genome medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic (chaperone) activity assay with multiple variants and dominant-negative validation, single lab but multiple orthogonal biochemical measurements","pmids":["28126021"],"is_preprint":false},{"year":2017,"finding":"In hypoxic colorectal cancer cells, HSPA1L interacts directly with the E3 ubiquitin ligase GP78, inhibiting GP78-mediated ubiquitination and proteasomal degradation of cellular prion protein (PrPC). HSPA1L knockdown restored GP78-PrPC interaction, increased PrPC ubiquitination, and reduced tumorigenicity in vivo.","method":"Co-immunoprecipitation, HSPA1L knockdown, in vivo tumor model, ubiquitination assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KD with defined molecular phenotype (ubiquitination, PrPC levels), and in vivo validation; single lab with multiple orthogonal methods","pmids":["28759037"],"is_preprint":false},{"year":2019,"finding":"MAPKAP kinase 2 (MK2) phosphorylates HspA1L specifically on Ser241 within the N-terminal nucleotide-binding domain. This phosphorylation event enhances HspA1L chaperone activity in vitro and renders male germ cells more resistant to heat stress-induced apoptosis.","method":"Proteomics-based substrate screen, in vitro kinase assay with site-directed mutagenesis (Ser241), chaperone activity assay, cell apoptosis assay under heat stress","journal":"Cell stress & chaperones","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site, plus in vitro chaperone activity assay and cellular phenotype; single lab with multiple orthogonal methods","pmids":["31642047"],"is_preprint":false},{"year":2020,"finding":"Melatonin upregulates HSPA1L in mesenchymal stem cells; HSPA1L binds cellular prion protein (PrPC), recruiting it to mitochondria. The HSPA1L-PrPC complex then binds COX4IA (mitochondrial complex IV), increasing mitochondrial membrane potential and anti-oxidant enzyme activity. HSPA1L knockdown blocked these protective effects.","method":"Co-immunoprecipitation, HSPA1L knockdown, mitochondrial fractionation, mitochondrial membrane potential measurement, murine hindlimb ischemia model","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding partners, KD with defined phenotype, in vivo model; single lab with multiple methods","pmids":["31965731"],"is_preprint":false},{"year":2020,"finding":"HSPA1L interacts directly with IGF1Rβ and integrin αV to form a triple complex that activates IGF1Rβ, driving AKT/NF-κB and AKT/GSK3β/β-catenin signaling. Additionally, HSPA1L translocates to the nucleus and binds directly to the β-catenin promoter to activate β-catenin transcription, promoting cancer stem cell-like properties and radiation resistance in NSCLC cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (promoter binding), HSPA1L overexpression/knockdown, signaling pathway analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex identification, ChIP for nuclear transcriptional role, and functional cellular assays; single lab","pmids":["32971893"],"is_preprint":false},{"year":2020,"finding":"Hspa1l knockout mice (generated by CRISPR/Cas9) are fertile and display no significant differences in spermatogenesis, apoptotic cell number in testes, epididymal histology, sperm count, or sperm motility compared to wild-type. Heat stress also did not exacerbate cell apoptosis in Hspa1l-/- testes, indicating HSPA1L is dispensable for physiological spermatogenesis and testicular heat stress responses in mice.","method":"CRISPR/Cas9 knockout, histological staining, immunofluorescence, TUNEL assay, sperm motility/count measurement, fertility testing, heat stress treatment","journal":"PeerJ","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with comprehensive phenotypic readouts (histology, apoptosis, fertility, heat stress); multiple orthogonal negative findings consistently replicated within study","pmids":["32231871"],"is_preprint":false},{"year":2021,"finding":"During internalization into proximal tubular cells, vaspin forms a complex with HSPA1L and GRP78; both vaspin-partners bind clathrin heavy chain and are involved in endocytosis. Overexpression of HSPA1L alleviated ER stress, autophagy impairment, and lysosome dysfunction in diabetic kidney disease models.","method":"Co-immunoprecipitation, HSPA1L overexpression, organelle stress assays (ER stress, autophagy, lysosome), in vivo vaspin-/- obese mouse model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying HSPA1L-vaspin-GRP78-clathrin complex, OE with defined organelle phenotype, in vivo model; single lab","pmids":["33742129"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 infection induces promoter hypomethylation of HSPA1L (with decreased DNMT1/3A/3B levels), leading to increased HSPA1L mRNA expression in COVID-19 patient blood samples, establishing epigenetic regulation of HSPA1L expression by viral infection.","method":"Promoter methylation analysis (bisulfite sequencing/pyrosequencing), mRNA quantification in patient blood, in vitro SARS-CoV-2 infection model, AZA (demethylating agent) treatment comparison","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation measurement correlated with expression in patient samples plus in vitro AZA validation; single lab with two orthogonal methods","pmids":["33679887"],"is_preprint":false},{"year":2024,"finding":"MFG-E8 interacts with HSPA1L (identified by immunoprecipitation and co-IP), and MFG-E8 overexpression downregulates Parkin via the HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic and senescent muscle cells.","method":"Immunoprecipitation, co-immunoprecipitation, MFG-E8 overexpression/siRNA, western blot for Parkin/PINK1/LC3B/P62","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying MFG-E8/HSPA1L interaction, pathway analysis by OE/KD with defined molecular phenotype; single lab","pmids":["38553831"],"is_preprint":false},{"year":2025,"finding":"VEGFR3 binds HSPA1L (identified by LC-MS/MS and Co-IP) and promotes crotonylation of HSPA1L at lysine 130 (K130). This K130 crotonylation is required for HSPA1L-mediated enhancement of PARKIN mitochondrial translocation and mitophagy. Mutating K130 to arginine (K130R) abolished VEGFR3's protective effects on mitophagy and oxidative stress in angiotensin II-induced proximal tubular cells.","method":"LC-MS/MS, co-immunoprecipitation, site-directed mutagenesis (K130R), PARKIN mitochondrial translocation assay, in vivo and in vitro Ang II models","journal":"Cell communication and signaling : CCS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — LC-MS/MS identification of interaction, co-IP confirmation, site-specific mutagenesis of PTM site with defined functional consequence; single lab with multiple orthogonal methods","pmids":["39875989"],"is_preprint":false},{"year":2026,"finding":"Hesperidin directly binds HSPA1L (identified by limited proteolysis mass spectrometry and molecular dynamics simulation), upregulates HSPA1L expression, and through this stabilizes GPX4 protein, suppressing UV-induced ferroptosis in keratinocytes and skin organoids.","method":"LiP-MS (limited proteolysis mass spectrometry), molecular dynamics simulation, transcriptomics, metabolomics, HSPA1L expression modulation, GPX4 stability assay in HaCaT cells and 3D skin organoids","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — LiP-MS for direct binding, plus functional validation in multiple cell models; single lab; chaperone stabilization of GPX4 inferred but not directly demonstrated by reconstitution","pmids":["42072126"],"is_preprint":false},{"year":2018,"finding":"In vitro functional experiments demonstrated a link between HSPA1L activity and decidualization of endometrial stromal cells, placing HSPA1L in the glucocorticoid receptor signaling pathway relevant to spontaneous preterm birth. A missense variant (rs34620296) was predicted in silico to generate an additional phosphorylation site that could affect chaperone activity or protein stability.","method":"In vitro decidualization assay with HSPA1L activity modulation; whole exome sequencing; in silico phosphorylation prediction","journal":"PLoS genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro functional link to decidualization reported but not mechanistically detailed in the abstract; in silico prediction only for phosphorylation site; single study","pmids":["30001343"],"is_preprint":false},{"year":2019,"finding":"Overexpression of the HSPA1L T allele (vs. C allele, corresponding to the +2437 polymorphism) in neuroblastoma cells and rat MCAO models reduced neuronal inhibition/infarct volume, decreased BAX expression, and increased PI3K and p-AKT, indicating HSPA1L protects against hypoxic/ischemic injury via the PI3K/AKT anti-apoptotic pathway, with the T allele conferring stronger neuroprotection than the C allele.","method":"Lentiviral overexpression of T and C alleles in SHSY5Y cells (hypoxia model) and rat MCAO model, TTC staining, western blot for Bax/PI3K/p-AKT/HSPA1L","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific OE in both in vitro and in vivo models with pathway protein measurements; single lab","pmids":["31170438"],"is_preprint":false}],"current_model":"HSPA1L (Hsp70-Hom) is a constitutively expressed cytoplasmic chaperone that translocates to the nucleus upon heat shock; its chaperone activity is enhanced by MK2-mediated phosphorylation at Ser241 and by VEGFR3-mediated crotonylation at K130; it forms functional complexes with cellular prion protein (PrPC), GP78, IGF1Rβ/integrin αV, vaspin/GRP78/clathrin, and MFG-E8, through which it regulates PrPC ubiquitination and stability, mitophagy via PARKIN translocation, IGF1Rβ/AKT signaling, endocytosis, and organelle homeostasis; it also acts as a nuclear transcription activator at the β-catenin promoter; loss-of-function mutations reduce chaperone activity and can exert dominant-negative effects, while Hspa1l knockout mice are fertile with normal spermatogenesis, indicating functional redundancy in the testis."},"narrative":{"mechanistic_narrative":"HSPA1L is a constitutively expressed cytoplasmic Hsp70-family chaperone that binds peptide substrates and relocates from the cytoplasm to the nucleus following heat shock [PMID:11599570]. Its chaperone activity is tuned by post-translational modification: MK2-mediated phosphorylation at Ser241 in the nucleotide-binding domain enhances chaperone function and protects germ cells from heat-induced apoptosis [PMID:31642047], and VEGFR3-driven crotonylation at Lys130 licenses HSPA1L to promote PARKIN mitochondrial translocation and mitophagy [PMID:39875989]. Through direct protein interactions HSPA1L acts as a hub coordinating protein stability and organelle homeostasis—it binds the E3 ligase GP78 to shield cellular prion protein (PrPC) from ubiquitination and degradation, thereby promoting tumorigenicity [PMID:28759037], and it engages IGF1Rβ and integrin αV to activate IGF1Rβ/AKT signaling while also entering the nucleus to bind the β-catenin promoter and activate β-catenin transcription, driving cancer stem-cell properties and radioresistance [PMID:32971893]. Rare HSPA1L variants reduce chaperone activity in vitro, and several act as dominant negatives against both HSPA1L and HSPA1A [PMID:28126021]. Despite these roles, Hspa1l-knockout mice are fertile with normal spermatogenesis and intact testicular heat-stress responses, indicating functional redundancy in vivo [PMID:32231871].","teleology":[{"year":2001,"claim":"Established the baseline biochemistry and behavior of HSPA1L by showing it is a bona fide peptide-binding chaperone that is cytoplasmic at rest and accumulates in the nucleus after heat shock.","evidence":"Peptide binding assay, immunolocalization/fractionation, and expression profiling in human cell lines","pmids":["11599570"],"confidence":"Medium","gaps":["No substrate specificity defined beyond model peptides","Nuclear function after heat-shock translocation not defined"]},{"year":2004,"claim":"Linked the peptide-binding domain of HSPA1L to immune modulation by showing an M493T polymorphism co-occurring with HLA-B*5701 is necessary for abacavir hypersensitivity.","evidence":"Fine genetic mapping, haplotype analysis, and ex vivo abacavir stimulation with CD8 depletion","pmids":["15024131"],"confidence":"Medium","gaps":["Direct biochemical mechanism of HSPA1L in antigen presentation not demonstrated","Genetic association does not isolate HSPA1L function from HLA context"]},{"year":2017,"claim":"Defined a chaperone-independent regulatory role by showing HSPA1L binds GP78 and blocks GP78-mediated ubiquitination of PrPC, stabilizing PrPC and promoting tumor growth.","evidence":"Reciprocal Co-IP, knockdown with ubiquitination readout, and in vivo tumor model in hypoxic colorectal cancer cells","pmids":["28759037"],"confidence":"High","gaps":["Whether HSPA1L sequesters GP78 or PrPC directly not resolved","Generality beyond hypoxic colorectal cancer untested"]},{"year":2019,"claim":"Identified a kinase-driven activation switch: MK2 phosphorylates HSPA1L at Ser241 in the nucleotide-binding domain, enhancing chaperone activity and conferring heat-stress resistance.","evidence":"Proteomic substrate screen, in vitro kinase assay with Ser241 mutagenesis, chaperone assay, and heat-stress apoptosis assay","pmids":["31642047"],"confidence":"High","gaps":["In vivo relevance to spermatogenesis not established (contrasts with KO phenotype)","Structural basis for activity enhancement unknown"]},{"year":2020,"claim":"Extended HSPA1L into mitochondrial protection by showing it recruits PrPC to mitochondria and the complex engages COX4IA to raise membrane potential and antioxidant capacity.","evidence":"Co-IP, knockdown, mitochondrial fractionation/membrane potential, and hindlimb ischemia model in mesenchymal stem cells","pmids":["31965731"],"confidence":"Medium","gaps":["Direct COX4IA binding by HSPA1L vs PrPC not separated","Single-lab Co-IP without reciprocal validation"]},{"year":2020,"claim":"Revealed a receptor-signaling and transcriptional role by showing HSPA1L forms an IGF1Rβ/integrin αV complex driving AKT signaling and directly activates the β-catenin promoter in the nucleus.","evidence":"Co-IP, ChIP for promoter binding, and overexpression/knockdown with signaling readouts in NSCLC cells","pmids":["32971893"],"confidence":"Medium","gaps":["Sequence-specific DNA binding by a chaperone not biochemically reconciled","Direct vs indirect promoter occupancy unresolved"]},{"year":2020,"claim":"Tested physiological necessity in vivo and found HSPA1L dispensable for spermatogenesis and testicular heat-stress responses, demonstrating functional redundancy.","evidence":"CRISPR/Cas9 knockout mice with histology, TUNEL, sperm counts, fertility testing, and heat-stress challenge","pmids":["32231871"],"confidence":"High","gaps":["Redundant paralog(s) compensating not identified","Phenotypes outside testis not assessed"]},{"year":2021,"claim":"Implicated HSPA1L in receptor endocytosis and organelle stress relief by showing it forms a vaspin/GRP78/clathrin complex and overexpression alleviates ER stress, autophagy, and lysosome dysfunction.","evidence":"Co-IP, overexpression, organelle stress assays, and vaspin-knockout obese mouse model in diabetic kidney disease","pmids":["33742129"],"confidence":"Medium","gaps":["Direct clathrin binding by HSPA1L not isolated from complex partners","Mechanism connecting endocytosis to organelle protection unclear"]},{"year":2021,"claim":"Established epigenetic control of HSPA1L expression by showing SARS-CoV-2 infection causes promoter hypomethylation and increased HSPA1L mRNA.","evidence":"Bisulfite/pyrosequencing methylation analysis, patient blood mRNA quantification, and AZA demethylation comparison","pmids":["33679887"],"confidence":"Medium","gaps":["Functional consequence of elevated HSPA1L in COVID-19 not determined","Correlative methylation-expression link in patient samples"]},{"year":2024,"claim":"Placed HSPA1L in mitophagy regulation by showing MFG-E8 binds HSPA1L and downregulates Parkin via an HSPA1L-Parkin axis, inhibiting mitophagy.","evidence":"Immunoprecipitation/Co-IP, MFG-E8 overexpression/siRNA, and western blots for mitophagy markers in diabetic/senescent muscle","pmids":["38553831"],"confidence":"Medium","gaps":["How HSPA1L controls Parkin levels mechanistically unknown","Single-lab Co-IP without orthogonal interaction validation"]},{"year":2025,"claim":"Identified a second activating PTM by showing VEGFR3-promoted crotonylation of HSPA1L at K130 is required for HSPA1L-driven PARKIN translocation and mitophagy.","evidence":"LC-MS/MS, Co-IP, K130R site-directed mutagenesis, PARKIN translocation assay, and Ang II models in proximal tubular cells","pmids":["39875989"],"confidence":"High","gaps":["Crotonyltransferase responsible not identified","How K130 crotonylation alters HSPA1L-PARKIN interaction unresolved"]},{"year":2026,"claim":"Connected HSPA1L to ferroptosis defense by showing the small molecule hesperidin binds and upregulates HSPA1L to stabilize GPX4 and suppress UV-induced ferroptosis.","evidence":"LiP-MS, molecular dynamics, and GPX4 stability assays in HaCaT keratinocytes and 3D skin organoids","pmids":["42072126"],"confidence":"Medium","gaps":["Direct chaperone stabilization of GPX4 not shown by reconstitution","Whether the effect requires chaperone activity not tested"]},{"year":null,"claim":"The structural and biochemical basis by which HSPA1L's PTMs (Ser241 phosphorylation, K130 crotonylation) reshape chaperone activity, and how a cytoplasmic chaperone achieves sequence-specific promoter binding, remain unresolved.","evidence":"No timeline discovery provides a structural model or reconstituted mechanism for these activities","pmids":[],"confidence":"Low","gaps":["No structural data on PTM-modified HSPA1L","Mechanism of nuclear DNA-binding by a chaperone unexplained","Identity of redundant paralog compensating in knockout mice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,11]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["GP78","PRNP","IGF1R","ITGAV","VASN","HSPA5","MFGE8","FLT4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P34931","full_name":"Heat shock 70 kDa protein 1-like","aliases":["Heat shock 70 kDa protein 1-Hom","HSP70-Hom","Heat shock protein family A member 1L"],"length_aa":641,"mass_kda":70.4,"function":"Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release (PubMed:26865365). Positive regulator of PRKN translocation to damaged mitochondria (PubMed:24270810)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P34931/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSPA1L","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BTF3","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"DNAJC8","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"HSPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HSPA1L","total_profiled":1310},"omim":[{"mim_id":"613035","title":"HEARING LOSS, NOISE-INDUCED, SUSCEPTIBILITY TO; NIHL","url":"https://www.omim.org/entry/613035"},{"mim_id":"608309","title":"PTEN-INDUCED KINASE 1; PINK1","url":"https://www.omim.org/entry/608309"},{"mim_id":"607980","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 7; TOMM7","url":"https://www.omim.org/entry/607980"},{"mim_id":"603884","title":"BAG COCHAPERONE 4; BAG4","url":"https://www.omim.org/entry/603884"},{"mim_id":"602544","title":"PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN","url":"https://www.omim.org/entry/602544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Annulus","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":54.8}],"url":"https://www.proteinatlas.org/search/HSPA1L"},"hgnc":{"alias_symbol":["HSP70-HOM","hum70t"],"prev_symbol":[]},"alphafold":{"accession":"P34931","domains":[{"cath_id":"3.30.420.40","chopping":"7-229_309-395","consensus_level":"medium","plddt":93.91,"start":7,"end":395},{"cath_id":"2.60.34.10","chopping":"401-512","consensus_level":"high","plddt":84.8247,"start":401,"end":512},{"cath_id":"1.20.1270.10","chopping":"515-614","consensus_level":"high","plddt":86.9047,"start":515,"end":614}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P34931","model_url":"https://alphafold.ebi.ac.uk/files/AF-P34931-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P34931-F1-predicted_aligned_error_v6.png","plddt_mean":88.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSPA1L","jax_strain_url":"https://www.jax.org/strain/search?query=HSPA1L"},"sequence":{"accession":"P34931","fasta_url":"https://rest.uniprot.org/uniprotkb/P34931.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P34931/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P34931"}},"corpus_meta":[{"pmid":"15024131","id":"PMC_15024131","title":"Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15024131","citation_count":336,"is_preprint":false},{"pmid":"7901896","id":"PMC_7901896","title":"Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM).","date":"1993","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7901896","citation_count":109,"is_preprint":false},{"pmid":"31965731","id":"PMC_31965731","title":"Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway.","date":"2020","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/31965731","citation_count":76,"is_preprint":false},{"pmid":"12544996","id":"PMC_12544996","title":"Heat shock protein 70 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22542718","citation_count":12,"is_preprint":false},{"pmid":"31642047","id":"PMC_31642047","title":"MAPKAP kinase 2-mediated phosphorylation of HspA1L protects male germ cells from heat stress-induced apoptosis.","date":"2019","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/31642047","citation_count":10,"is_preprint":false},{"pmid":"20096741","id":"PMC_20096741","title":"Synergistic effect and VEGF/HSP70-hom haplotype analysis: relationship to prostate cancer risk and clinical outcome.","date":"2010","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20096741","citation_count":10,"is_preprint":false},{"pmid":"31228677","id":"PMC_31228677","title":"HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with idiopathic male infertility in Iranian population.","date":"2019","source":"European journal of obstetrics, gynecology, and reproductive 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The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/26160076","citation_count":5,"is_preprint":false},{"pmid":"16525348","id":"PMC_16525348","title":"Polymorphisms of heat shock protein-70 (HSPA1B and HSPA1L loci) do not influence infection or outcome risk in critically ill surgical patients.","date":"2006","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/16525348","citation_count":5,"is_preprint":false},{"pmid":"25044062","id":"PMC_25044062","title":"HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance.","date":"2014","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25044062","citation_count":4,"is_preprint":false},{"pmid":"25680846","id":"PMC_25680846","title":"Elevated level of HSPA1L mRNA correlates with graft-versus-host disease.","date":"2015","source":"Transplant immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25680846","citation_count":4,"is_preprint":false},{"pmid":"19758266","id":"PMC_19758266","title":"Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation.","date":"2010","source":"Clinical transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/19758266","citation_count":3,"is_preprint":false},{"pmid":"32039449","id":"PMC_32039449","title":"HSPA1L rs1061581 polymorphism is associated with the risk of preeclampsia in Han Chinese women.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32039449","citation_count":0,"is_preprint":false},{"pmid":"27062781","id":"PMC_27062781","title":"[Interaction Between Occupational Vanadium Exposure and hsp70-hom on Neurobehavioral Function].","date":"2016","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. 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HSPA1L knockdown restored GP78-PrPC interaction, increased PrPC ubiquitination, and reduced tumorigenicity in vivo.\",\n      \"method\": \"Co-immunoprecipitation, HSPA1L knockdown, in vivo tumor model, ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KD with defined molecular phenotype (ubiquitination, PrPC levels), and in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28759037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAPKAP kinase 2 (MK2) phosphorylates HspA1L specifically on Ser241 within the N-terminal nucleotide-binding domain. This phosphorylation event enhances HspA1L chaperone activity in vitro and renders male germ cells more resistant to heat stress-induced apoptosis.\",\n      \"method\": \"Proteomics-based substrate screen, in vitro kinase assay with site-directed mutagenesis (Ser241), chaperone activity assay, cell apoptosis assay under heat stress\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site, plus in vitro chaperone activity assay and cellular phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31642047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Melatonin upregulates HSPA1L in mesenchymal stem cells; HSPA1L binds cellular prion protein (PrPC), recruiting it to mitochondria. The HSPA1L-PrPC complex then binds COX4IA (mitochondrial complex IV), increasing mitochondrial membrane potential and anti-oxidant enzyme activity. HSPA1L knockdown blocked these protective effects.\",\n      \"method\": \"Co-immunoprecipitation, HSPA1L knockdown, mitochondrial fractionation, mitochondrial membrane potential measurement, murine hindlimb ischemia model\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding partners, KD with defined phenotype, in vivo model; single lab with multiple methods\",\n      \"pmids\": [\"31965731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPA1L interacts directly with IGF1Rβ and integrin αV to form a triple complex that activates IGF1Rβ, driving AKT/NF-κB and AKT/GSK3β/β-catenin signaling. Additionally, HSPA1L translocates to the nucleus and binds directly to the β-catenin promoter to activate β-catenin transcription, promoting cancer stem cell-like properties and radiation resistance in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (promoter binding), HSPA1L overexpression/knockdown, signaling pathway analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex identification, ChIP for nuclear transcriptional role, and functional cellular assays; single lab\",\n      \"pmids\": [\"32971893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hspa1l knockout mice (generated by CRISPR/Cas9) are fertile and display no significant differences in spermatogenesis, apoptotic cell number in testes, epididymal histology, sperm count, or sperm motility compared to wild-type. Heat stress also did not exacerbate cell apoptosis in Hspa1l-/- testes, indicating HSPA1L is dispensable for physiological spermatogenesis and testicular heat stress responses in mice.\",\n      \"method\": \"CRISPR/Cas9 knockout, histological staining, immunofluorescence, TUNEL assay, sperm motility/count measurement, fertility testing, heat stress treatment\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with comprehensive phenotypic readouts (histology, apoptosis, fertility, heat stress); multiple orthogonal negative findings consistently replicated within study\",\n      \"pmids\": [\"32231871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During internalization into proximal tubular cells, vaspin forms a complex with HSPA1L and GRP78; both vaspin-partners bind clathrin heavy chain and are involved in endocytosis. Overexpression of HSPA1L alleviated ER stress, autophagy impairment, and lysosome dysfunction in diabetic kidney disease models.\",\n      \"method\": \"Co-immunoprecipitation, HSPA1L overexpression, organelle stress assays (ER stress, autophagy, lysosome), in vivo vaspin-/- obese mouse model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying HSPA1L-vaspin-GRP78-clathrin complex, OE with defined organelle phenotype, in vivo model; single lab\",\n      \"pmids\": [\"33742129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 infection induces promoter hypomethylation of HSPA1L (with decreased DNMT1/3A/3B levels), leading to increased HSPA1L mRNA expression in COVID-19 patient blood samples, establishing epigenetic regulation of HSPA1L expression by viral infection.\",\n      \"method\": \"Promoter methylation analysis (bisulfite sequencing/pyrosequencing), mRNA quantification in patient blood, in vitro SARS-CoV-2 infection model, AZA (demethylating agent) treatment comparison\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation measurement correlated with expression in patient samples plus in vitro AZA validation; single lab with two orthogonal methods\",\n      \"pmids\": [\"33679887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MFG-E8 interacts with HSPA1L (identified by immunoprecipitation and co-IP), and MFG-E8 overexpression downregulates Parkin via the HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic and senescent muscle cells.\",\n      \"method\": \"Immunoprecipitation, co-immunoprecipitation, MFG-E8 overexpression/siRNA, western blot for Parkin/PINK1/LC3B/P62\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying MFG-E8/HSPA1L interaction, pathway analysis by OE/KD with defined molecular phenotype; single lab\",\n      \"pmids\": [\"38553831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VEGFR3 binds HSPA1L (identified by LC-MS/MS and Co-IP) and promotes crotonylation of HSPA1L at lysine 130 (K130). This K130 crotonylation is required for HSPA1L-mediated enhancement of PARKIN mitochondrial translocation and mitophagy. Mutating K130 to arginine (K130R) abolished VEGFR3's protective effects on mitophagy and oxidative stress in angiotensin II-induced proximal tubular cells.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, site-directed mutagenesis (K130R), PARKIN mitochondrial translocation assay, in vivo and in vitro Ang II models\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — LC-MS/MS identification of interaction, co-IP confirmation, site-specific mutagenesis of PTM site with defined functional consequence; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39875989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Hesperidin directly binds HSPA1L (identified by limited proteolysis mass spectrometry and molecular dynamics simulation), upregulates HSPA1L expression, and through this stabilizes GPX4 protein, suppressing UV-induced ferroptosis in keratinocytes and skin organoids.\",\n      \"method\": \"LiP-MS (limited proteolysis mass spectrometry), molecular dynamics simulation, transcriptomics, metabolomics, HSPA1L expression modulation, GPX4 stability assay in HaCaT cells and 3D skin organoids\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — LiP-MS for direct binding, plus functional validation in multiple cell models; single lab; chaperone stabilization of GPX4 inferred but not directly demonstrated by reconstitution\",\n      \"pmids\": [\"42072126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In vitro functional experiments demonstrated a link between HSPA1L activity and decidualization of endometrial stromal cells, placing HSPA1L in the glucocorticoid receptor signaling pathway relevant to spontaneous preterm birth. A missense variant (rs34620296) was predicted in silico to generate an additional phosphorylation site that could affect chaperone activity or protein stability.\",\n      \"method\": \"In vitro decidualization assay with HSPA1L activity modulation; whole exome sequencing; in silico phosphorylation prediction\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro functional link to decidualization reported but not mechanistically detailed in the abstract; in silico prediction only for phosphorylation site; single study\",\n      \"pmids\": [\"30001343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of the HSPA1L T allele (vs. C allele, corresponding to the +2437 polymorphism) in neuroblastoma cells and rat MCAO models reduced neuronal inhibition/infarct volume, decreased BAX expression, and increased PI3K and p-AKT, indicating HSPA1L protects against hypoxic/ischemic injury via the PI3K/AKT anti-apoptotic pathway, with the T allele conferring stronger neuroprotection than the C allele.\",\n      \"method\": \"Lentiviral overexpression of T and C alleles in SHSY5Y cells (hypoxia model) and rat MCAO model, TTC staining, western blot for Bax/PI3K/p-AKT/HSPA1L\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific OE in both in vitro and in vivo models with pathway protein measurements; single lab\",\n      \"pmids\": [\"31170438\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPA1L (Hsp70-Hom) is a constitutively expressed cytoplasmic chaperone that translocates to the nucleus upon heat shock; its chaperone activity is enhanced by MK2-mediated phosphorylation at Ser241 and by VEGFR3-mediated crotonylation at K130; it forms functional complexes with cellular prion protein (PrPC), GP78, IGF1Rβ/integrin αV, vaspin/GRP78/clathrin, and MFG-E8, through which it regulates PrPC ubiquitination and stability, mitophagy via PARKIN translocation, IGF1Rβ/AKT signaling, endocytosis, and organelle homeostasis; it also acts as a nuclear transcription activator at the β-catenin promoter; loss-of-function mutations reduce chaperone activity and can exert dominant-negative effects, while Hspa1l knockout mice are fertile with normal spermatogenesis, indicating functional redundancy in the testis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HSPA1L is a constitutively expressed cytoplasmic Hsp70-family chaperone that binds peptide substrates and relocates from the cytoplasm to the nucleus following heat shock [#0]. Its chaperone activity is tuned by post-translational modification: MK2-mediated phosphorylation at Ser241 in the nucleotide-binding domain enhances chaperone function and protects germ cells from heat-induced apoptosis [#4], and VEGFR3-driven crotonylation at Lys130 licenses HSPA1L to promote PARKIN mitochondrial translocation and mitophagy [#11]. Through direct protein interactions HSPA1L acts as a hub coordinating protein stability and organelle homeostasis—it binds the E3 ligase GP78 to shield cellular prion protein (PrPC) from ubiquitination and degradation, thereby promoting tumorigenicity [#3], and it engages IGF1Rβ and integrin αV to activate IGF1Rβ/AKT signaling while also entering the nucleus to bind the β-catenin promoter and activate β-catenin transcription, driving cancer stem-cell properties and radioresistance [#6]. Rare HSPA1L variants reduce chaperone activity in vitro, and several act as dominant negatives against both HSPA1L and HSPA1A [#2]. Despite these roles, Hspa1l-knockout mice are fertile with normal spermatogenesis and intact testicular heat-stress responses, indicating functional redundancy in vivo [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the baseline biochemistry and behavior of HSPA1L by showing it is a bona fide peptide-binding chaperone that is cytoplasmic at rest and accumulates in the nucleus after heat shock.\",\n      \"evidence\": \"Peptide binding assay, immunolocalization/fractionation, and expression profiling in human cell lines\",\n      \"pmids\": [\"11599570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate specificity defined beyond model peptides\", \"Nuclear function after heat-shock translocation not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked the peptide-binding domain of HSPA1L to immune modulation by showing an M493T polymorphism co-occurring with HLA-B*5701 is necessary for abacavir hypersensitivity.\",\n      \"evidence\": \"Fine genetic mapping, haplotype analysis, and ex vivo abacavir stimulation with CD8 depletion\",\n      \"pmids\": [\"15024131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of HSPA1L in antigen presentation not demonstrated\", \"Genetic association does not isolate HSPA1L function from HLA context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a chaperone-independent regulatory role by showing HSPA1L binds GP78 and blocks GP78-mediated ubiquitination of PrPC, stabilizing PrPC and promoting tumor growth.\",\n      \"evidence\": \"Reciprocal Co-IP, knockdown with ubiquitination readout, and in vivo tumor model in hypoxic colorectal cancer cells\",\n      \"pmids\": [\"28759037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSPA1L sequesters GP78 or PrPC directly not resolved\", \"Generality beyond hypoxic colorectal cancer untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a kinase-driven activation switch: MK2 phosphorylates HSPA1L at Ser241 in the nucleotide-binding domain, enhancing chaperone activity and conferring heat-stress resistance.\",\n      \"evidence\": \"Proteomic substrate screen, in vitro kinase assay with Ser241 mutagenesis, chaperone assay, and heat-stress apoptosis assay\",\n      \"pmids\": [\"31642047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to spermatogenesis not established (contrasts with KO phenotype)\", \"Structural basis for activity enhancement unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended HSPA1L into mitochondrial protection by showing it recruits PrPC to mitochondria and the complex engages COX4IA to raise membrane potential and antioxidant capacity.\",\n      \"evidence\": \"Co-IP, knockdown, mitochondrial fractionation/membrane potential, and hindlimb ischemia model in mesenchymal stem cells\",\n      \"pmids\": [\"31965731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct COX4IA binding by HSPA1L vs PrPC not separated\", \"Single-lab Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a receptor-signaling and transcriptional role by showing HSPA1L forms an IGF1Rβ/integrin αV complex driving AKT signaling and directly activates the β-catenin promoter in the nucleus.\",\n      \"evidence\": \"Co-IP, ChIP for promoter binding, and overexpression/knockdown with signaling readouts in NSCLC cells\",\n      \"pmids\": [\"32971893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence-specific DNA binding by a chaperone not biochemically reconciled\", \"Direct vs indirect promoter occupancy unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tested physiological necessity in vivo and found HSPA1L dispensable for spermatogenesis and testicular heat-stress responses, demonstrating functional redundancy.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mice with histology, TUNEL, sperm counts, fertility testing, and heat-stress challenge\",\n      \"pmids\": [\"32231871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundant paralog(s) compensating not identified\", \"Phenotypes outside testis not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated HSPA1L in receptor endocytosis and organelle stress relief by showing it forms a vaspin/GRP78/clathrin complex and overexpression alleviates ER stress, autophagy, and lysosome dysfunction.\",\n      \"evidence\": \"Co-IP, overexpression, organelle stress assays, and vaspin-knockout obese mouse model in diabetic kidney disease\",\n      \"pmids\": [\"33742129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct clathrin binding by HSPA1L not isolated from complex partners\", \"Mechanism connecting endocytosis to organelle protection unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established epigenetic control of HSPA1L expression by showing SARS-CoV-2 infection causes promoter hypomethylation and increased HSPA1L mRNA.\",\n      \"evidence\": \"Bisulfite/pyrosequencing methylation analysis, patient blood mRNA quantification, and AZA demethylation comparison\",\n      \"pmids\": [\"33679887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of elevated HSPA1L in COVID-19 not determined\", \"Correlative methylation-expression link in patient samples\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed HSPA1L in mitophagy regulation by showing MFG-E8 binds HSPA1L and downregulates Parkin via an HSPA1L-Parkin axis, inhibiting mitophagy.\",\n      \"evidence\": \"Immunoprecipitation/Co-IP, MFG-E8 overexpression/siRNA, and western blots for mitophagy markers in diabetic/senescent muscle\",\n      \"pmids\": [\"38553831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPA1L controls Parkin levels mechanistically unknown\", \"Single-lab Co-IP without orthogonal interaction validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a second activating PTM by showing VEGFR3-promoted crotonylation of HSPA1L at K130 is required for HSPA1L-driven PARKIN translocation and mitophagy.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, K130R site-directed mutagenesis, PARKIN translocation assay, and Ang II models in proximal tubular cells\",\n      \"pmids\": [\"39875989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crotonyltransferase responsible not identified\", \"How K130 crotonylation alters HSPA1L-PARKIN interaction unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected HSPA1L to ferroptosis defense by showing the small molecule hesperidin binds and upregulates HSPA1L to stabilize GPX4 and suppress UV-induced ferroptosis.\",\n      \"evidence\": \"LiP-MS, molecular dynamics, and GPX4 stability assays in HaCaT keratinocytes and 3D skin organoids\",\n      \"pmids\": [\"42072126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chaperone stabilization of GPX4 not shown by reconstitution\", \"Whether the effect requires chaperone activity not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and biochemical basis by which HSPA1L's PTMs (Ser241 phosphorylation, K130 crotonylation) reshape chaperone activity, and how a cytoplasmic chaperone achieves sequence-specific promoter binding, remain unresolved.\",\n      \"evidence\": \"No timeline discovery provides a structural model or reconstituted mechanism for these activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data on PTM-modified HSPA1L\", \"Mechanism of nuclear DNA-binding by a chaperone unexplained\", \"Identity of redundant paralog compensating in knockout mice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009612\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GP78\", \"PRNP\", \"IGF1R\", \"ITGAV\", \"VASN\", \"HSPA5\", \"MFGE8\", \"FLT4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}