{"gene":"HSPA1L","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2001,"finding":"HSPA1L (Hsp70-Hom) was shown to have peptide-binding specificity, is endogenously expressed in human cell lines, localizes to the cytoplasm under basal conditions and concentrates in the nucleus after heat shock, and is specifically upregulated by interferon-gamma and LPS treatment.","method":"Peptide binding assays, immunofluorescence, subcellular fractionation, western blotting, RT-PCR across tissues and cell lines","journal":"Cell stress & chaperones","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (binding assay, localization, expression regulation) in a single characterization study","pmids":["11599570"],"is_preprint":false},{"year":2019,"finding":"MAPKAP kinase 2 (MK2) phosphorylates HspA1L specifically on Ser241 within the N-terminal nucleotide-binding domain, and this phosphorylation enhances HspA1L chaperone activity in vitro and protects male germ cells from heat stress-induced apoptosis.","method":"Proteomics-based substrate screen, in vitro kinase assay, site-directed mutagenesis, chaperone activity assay, cell viability/apoptosis assays in germ cells","journal":"Cell stress & chaperones","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis identifying specific phosphorylation site, validated functional consequence","pmids":["31642047"],"is_preprint":false},{"year":2017,"finding":"In hypoxic colorectal cancer cells, HSPA1L interacts with the E3 ubiquitin ligase GP78 and inhibits GP78-mediated ubiquitination and degradation of cellular prion protein (PrPC), thereby promoting PrPC accumulation and tumor progression; HSPA1L knockdown restored GP78-PrPC interaction and increased PrPC ubiquitination.","method":"Co-immunoprecipitation, knockdown (siRNA), ubiquitination assay, in vivo xenograft, western blotting","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying binding partners, knockdown with defined molecular and in vivo phenotypic readouts, multiple orthogonal methods","pmids":["28759037"],"is_preprint":false},{"year":2017,"finding":"De novo and rare missense mutations in HSPA1L identified in IBD patients result in decreased chaperone activity in vitro; three variants also showed dominant negative effects on both HSPA1L and HSPA1A chaperone activity. In vitro functional assay linked HSPA1L activity to decidualization.","method":"Whole exome sequencing, in vitro chaperone activity biochemical assay of variant proteins, dominant negative assay","journal":"Genome medicine","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro biochemical assay of multiple variant proteins with mutagenesis-equivalent functional comparison","pmids":["28126021"],"is_preprint":false},{"year":2020,"finding":"Melatonin-induced HSPA1L binds to cellular prion protein (PrPC), recruits PrPC to mitochondria, and the HSPA1L-PrPC complex then binds to COX4I (mitochondrial complex IV protein), increasing mitochondrial membrane potential and antioxidant enzyme activity; HSPA1L knockdown blocked these protective effects and abrogated melatonin-mediated rescue of mitophagy in senescent MSCs.","method":"Co-immunoprecipitation, siRNA knockdown, mitochondrial fractionation, mitochondrial membrane potential assay, ROS/antioxidant assay, murine hindlimb ischemia model","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying protein complex, knockdown with defined molecular and in vivo functional phenotype, multiple orthogonal 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 signaling through AKT/NF-κB and AKT/GSK3β/β-catenin pathways; additionally, HSPA1L is present in the nucleus and directly binds the β-catenin promoter to function as a transcriptional activator, regulating ALDH1 expression and cancer stem cell properties in NSCLC cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), knockdown/overexpression, reporter assays, flow cytometry for ALDH1","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ChIP identifying binding and transcriptional activity, single lab study","pmids":["32971893"],"is_preprint":false},{"year":2021,"finding":"During internalization into proximal tubular cells, vaspin forms a complex with HSPA1L and GRP78; both vaspin partners bind to clathrin heavy chain and are involved in endocytosis. Overexpression of HSPA1L alleviated organelle stresses (ER stress, autophagy impairment, lysosome dysfunction) in diabetic kidney disease.","method":"Co-immunoprecipitation, overexpression, vaspin-/- mouse model, organelle stress assays (ER, lysosome, autophagy markers)","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP identifying complex components, overexpression with defined cellular phenotype, in vivo knockout model","pmids":["33742129"],"is_preprint":false},{"year":2024,"finding":"MFG-E8 interacts with HSPA1L (identified by Co-IP), and elevated MFG-E8 downregulates Parkin expression via the HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia; disruption of this pathway by MFG-E8 siRNA rescued mitophagy.","method":"Immunoprecipitation, Co-immunoprecipitation, siRNA knockdown, western blotting, in vivo mouse model","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP identifying interaction, pathway placement by knockdown with defined phenotype, single lab","pmids":["38553831"],"is_preprint":false},{"year":2025,"finding":"VEGFR3 binds directly to HSPA1L via its disorder domain (identified by LC-MS/MS and Co-IP), and crotonylation of HSPA1L at K130 by VEGFR3 is required for promoting PARKIN mitochondrial translocation and PARKIN-dependent mitophagy; K130R mutation abolished these protective effects in Ang II-induced proximal tubular cells.","method":"LC-MS/MS, Co-immunoprecipitation, site-directed mutagenesis (K130R), in vitro and in vivo (Ang II mouse model) functional assays","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1-2 — MS identification of interaction and PTM site, mutagenesis validation, in vivo and in vitro orthogonal evidence","pmids":["39875989"],"is_preprint":false},{"year":2004,"finding":"A nonsynonymous polymorphism in HSPA1L (M493T, in the peptide-binding domain) in combination with HLA-B*5701 was identified as necessary for abacavir hypersensitivity; abacavir-stimulated monocyte TNF expression was abrogated by CD8+ T cell depletion, indicating an HLA-B*5701-restricted immune mechanism.","method":"Fine genetic mapping, haplotype analysis, ex vivo abacavir stimulation with CD8+ T cell depletion, cohort study","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 — genetic mapping with ex vivo functional assay; identifies domain relevance (peptide-binding subunit) but no direct biochemical reconstitution of variant function","pmids":["15024131"],"is_preprint":false},{"year":2018,"finding":"Rare, likely damaging missense variants in HSPA1L were identified in families with recurrent spontaneous preterm birth; in silico analysis predicted an additional phosphorylation site from rs34620296 that could affect chaperone activity or protein stability, and in vitro functional experiments showed a link between HSPA1L activity and decidualization.","method":"Whole exome sequencing, in silico phosphorylation prediction, in vitro decidualization functional assay","journal":"PLoS genetics","confidence":"Low","confidence_rationale":"Tier 3-4 — genetic mapping with limited in vitro functional follow-up; mechanistic link to decidualization not fully characterized","pmids":["30001343"],"is_preprint":false},{"year":2019,"finding":"Overexpression of HSPA1L (either C or T allele of +2437 SNP) in neuroblastoma cells and rat MCAO model reduced neuronal apoptosis under hypoxia/ischemia by upregulating PI3K/p-AKT and downregulating BAX; the T allele showed stronger neuroprotection than the C allele.","method":"Lentiviral overexpression, neuronal hypoxic injury model (DFO), rat MCAO model, TTC staining, western blotting for apoptotic proteins","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2-3 — overexpression in both in vitro and in vivo models with defined molecular pathway readouts, single lab","pmids":["31170438"],"is_preprint":false},{"year":2020,"finding":"Hspa1l knockout mice (CRISPR/Cas9) show no defect in spermatogenesis, sperm count, sperm motility, or fertility, and heat stress does not exacerbate testicular apoptosis in Hspa1l-/- mice, demonstrating that HSPA1L is dispensable for physiological spermatogenesis and heat stress responses in the testis.","method":"CRISPR/Cas9 knockout, histology, TUNEL assay, sperm motility and count analysis, fertility testing, heat stress challenge","journal":"PeerJ","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined phenotypic readouts and heat stress challenge, strong negative result","pmids":["32231871"],"is_preprint":false}],"current_model":"HSPA1L is a constitutively expressed MHC-linked HSP70 family chaperone that localizes to the cytoplasm (and nucleus under heat shock), binds peptides via its C-terminal domain, is phosphorylated by MK2 at Ser241 to enhance chaperone activity under stress, and participates in multiple protein complexes (with PrPC/COX4I at mitochondria, GP78, IGF1Rβ/integrin αV, vaspin/GRP78/clathrin, and VEGFR3) to regulate mitophagy, proteasomal degradation, receptor signaling, and organelle homeostasis, while being dispensable for spermatogenesis."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that HSPA1L is a constitutively expressed, peptide-binding HSP70 family member with regulated subcellular localization answered the basic question of whether this MHC-linked chaperone is functionally active and inducible.","evidence":"Peptide-binding assays, immunofluorescence, and expression profiling across human cell lines and tissues","pmids":["11599570"],"confidence":"High","gaps":["Endogenous client proteins not identified","Mechanism of nuclear translocation under heat shock not defined","No comparison of chaperone efficiency relative to HSPA1A/HSPA1B"]},{"year":2004,"claim":"Genetic mapping linked the HSPA1L M493T polymorphism in the peptide-binding domain, in combination with HLA-B*5701, to abacavir hypersensitivity, providing the first evidence that HSPA1L peptide-binding variation has immunological consequences.","evidence":"Fine genetic mapping, haplotype analysis, and ex vivo abacavir-stimulated TNF assay with CD8+ T cell depletion in patient cohorts","pmids":["15024131"],"confidence":"Medium","gaps":["No biochemical reconstitution showing how M493T alters peptide presentation","Contribution of HSPA1L versus HLA-B*5701 not individually resolved","No structural basis for altered peptide binding"]},{"year":2017,"claim":"Demonstrating that HSPA1L binds GP78 and blocks GP78-mediated ubiquitination of PrPC established HSPA1L as a regulator of the ubiquitin-proteasome pathway, linking chaperone activity to protein turnover and tumor progression under hypoxia.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown, ubiquitination assays, and in vivo xenograft in colorectal cancer cells","pmids":["28759037"],"confidence":"High","gaps":["Structural basis of HSPA1L-GP78 interaction unknown","Whether HSPA1L regulates GP78 activity toward other substrates not tested","Hypoxia-dependent regulation of HSPA1L expression mechanism not defined"]},{"year":2017,"claim":"Identification of rare missense HSPA1L variants with decreased or dominant-negative chaperone activity in IBD patients established that HSPA1L functional variation has disease relevance and that its chaperone activity can be quantitatively assessed in vitro.","evidence":"Whole exome sequencing of IBD patients with in vitro biochemical chaperone activity assays of purified variant proteins","pmids":["28126021"],"confidence":"High","gaps":["Causal relationship between HSPA1L variants and IBD pathogenesis not established","Dominant-negative mechanism not structurally explained","Decidualization link not mechanistically characterized"]},{"year":2019,"claim":"Identification of MK2-dependent phosphorylation at Ser241 that enhances chaperone activity defined a stress-activated post-translational regulatory mechanism for HSPA1L, explaining how its activity is tuned during cellular stress.","evidence":"Proteomics substrate screen, in vitro kinase assay, Ser241 mutagenesis, chaperone activity assay, and germ cell apoptosis assays","pmids":["31642047"],"confidence":"High","gaps":["Whether Ser241 phosphorylation affects client specificity unknown","In vivo relevance of this phosphosite not confirmed in animal models","Dephosphorylation mechanism not identified"]},{"year":2020,"claim":"Showing that HSPA1L recruits PrPC to mitochondria and forms a ternary complex with COX4I to enhance mitochondrial function and regulate mitophagy established HSPA1L as a mitochondrial homeostasis factor in mesenchymal stem cells.","evidence":"Co-immunoprecipitation, mitochondrial fractionation, membrane potential and ROS assays, siRNA knockdown, and murine hindlimb ischemia model","pmids":["31965731"],"confidence":"High","gaps":["How HSPA1L is directed to mitochondria not defined","Whether the HSPA1L-PrPC-COX4I complex forms in cell types other than MSCs unknown","Melatonin-dependent induction mechanism upstream of HSPA1L not characterized"]},{"year":2020,"claim":"HSPA1L was shown to interact with IGF1Rβ and integrin αV, activating AKT/NF-κB and AKT/GSK3β/β-catenin signaling, and to directly bind the β-catenin promoter, revealing a dual cytoplasmic–nuclear role in cancer stemness.","evidence":"Co-immunoprecipitation, ChIP, reporter assays, knockdown/overexpression in NSCLC cells","pmids":["32971893"],"confidence":"Medium","gaps":["Transcription factor activity not confirmed by DNA-binding domain mapping","Whether nuclear HSPA1L transcriptional activity is chaperone-dependent unknown","Single-lab finding awaits independent validation"]},{"year":2020,"claim":"CRISPR knockout demonstrated that HSPA1L is dispensable for spermatogenesis and testicular heat-stress protection, resolving a long-standing assumption based on its high testicular expression.","evidence":"Hspa1l−/− mice generated by CRISPR/Cas9 with histology, TUNEL, sperm analysis, fertility testing, and heat-stress challenge","pmids":["32231871"],"confidence":"High","gaps":["Compensatory upregulation of other HSP70 family members not fully assessed","Phenotypes under non-heat stresses (e.g., oxidative, proteotoxic) not tested","Tissue-specific conditional KO not performed"]},{"year":2021,"claim":"Identification of a vaspin–HSPA1L–GRP78–clathrin complex in proximal tubular cells linked HSPA1L to clathrin-mediated endocytosis and organelle stress protection in diabetic kidney disease.","evidence":"Co-immunoprecipitation, HSPA1L overexpression, vaspin-knockout mouse model, ER/lysosome/autophagy stress markers","pmids":["33742129"],"confidence":"Medium","gaps":["Direct binding between HSPA1L and clathrin not confirmed by binary assay","How HSPA1L alleviates ER stress mechanistically is not defined","Stoichiometry and stability of the vaspin–HSPA1L–GRP78 complex not characterized"]},{"year":2024,"claim":"MFG-E8 was shown to interact with HSPA1L and suppress Parkin expression through an HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia, positioning HSPA1L as a node linking extracellular signals to mitophagy regulation.","evidence":"Co-immunoprecipitation, siRNA knockdown, western blotting, diabetic sarcopenia mouse model","pmids":["38553831"],"confidence":"Medium","gaps":["Mechanism by which HSPA1L-MFG-E8 interaction downregulates Parkin is unknown","Whether HSPA1L directly binds Parkin or acts indirectly not resolved","Single-lab finding"]},{"year":2025,"claim":"VEGFR3-mediated crotonylation of HSPA1L at K130 was shown to be required for PARKIN mitochondrial translocation and mitophagy, establishing a novel post-translational modification that governs HSPA1L's mitophagy-regulatory function.","evidence":"LC-MS/MS identification of interaction and K130 crotonylation site, K130R mutagenesis, co-immunoprecipitation, Ang II-induced injury models in vitro and in vivo","pmids":["39875989"],"confidence":"High","gaps":["Enzyme catalyzing K130 crotonylation not identified (VEGFR3 is a kinase, not a known crotonyltransferase)","Whether K130 crotonylation affects chaperone activity per se not tested","Structural basis for crotonylation-dependent PARKIN recruitment unknown"]},{"year":null,"claim":"The relationship between HSPA1L's multiple post-translational modifications (Ser241 phosphorylation, K130 crotonylation), its client specificity across cellular contexts, and its apparently redundant role in spermatogenesis remains unintegrated into a unified regulatory model.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of HSPA1L with bound clients or in modified states","Systematic identification of endogenous substrates/clients not performed","Functional redundancy with HSPA1A/HSPA1B not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6]}],"complexes":["HSPA1L-PrPC-COX4I mitochondrial complex","vaspin-HSPA1L-GRP78-clathrin complex","HSPA1L-IGF1Rβ-integrin αV complex"],"partners":["GP78","PRNP","COX4I1","IGF1R","ITGAV","HSPA5","FLT4","MFGE8"],"other_free_text":[]},"mechanistic_narrative":"HSPA1L is a constitutively expressed, MHC class III-linked member of the HSP70 chaperone family that functions as a cytoplasmic and stress-responsive nuclear chaperone with roles in protein quality control, mitophagy regulation, and receptor signaling. It binds peptides via its C-terminal substrate-binding domain, is phosphorylated by MK2 at Ser241 to enhance chaperone activity under heat stress, and undergoes crotonylation at K130 by VEGFR3 to promote PARKIN mitochondrial translocation and PARKIN-dependent mitophagy [PMID:11599570, PMID:31642047, PMID:39875989]. HSPA1L modulates protein stability by competitively inhibiting GP78-mediated ubiquitination of PrPC, forms a complex with PrPC and COX4I at mitochondria to sustain mitochondrial membrane potential, and interacts with IGF1Rβ/integrin αV to activate AKT signaling while also directly binding the β-catenin promoter as a transcriptional activator [PMID:28759037, PMID:31965731, PMID:32971893]. Despite high testicular expression, HSPA1L is dispensable for spermatogenesis and testicular heat-stress responses in knockout mice [PMID:32231871]."},"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":74,"is_preprint":false},{"pmid":"12544996","id":"PMC_12544996","title":"Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations and interfere with outcome after major injury.","date":"2003","source":"Critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12544996","citation_count":62,"is_preprint":false},{"pmid":"15818324","id":"PMC_15818324","title":"HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease.","date":"2005","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/15818324","citation_count":40,"is_preprint":false},{"pmid":"30001343","id":"PMC_30001343","title":"Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30001343","citation_count":38,"is_preprint":false},{"pmid":"33679887","id":"PMC_33679887","title":"SARS-CoV-2 Infection-Induced Promoter Hypomethylation as an Epigenetic Modulator of Heat Shock Protein A1L (HSPA1L) Gene.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33679887","citation_count":35,"is_preprint":false},{"pmid":"28759037","id":"PMC_28759037","title":"Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28759037","citation_count":35,"is_preprint":false},{"pmid":"27614828","id":"PMC_27614828","title":"Modification of embryonic resistance to heat shock in cattle by melatonin and genetic variation in HSPA1L.","date":"2016","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/27614828","citation_count":35,"is_preprint":false},{"pmid":"11599570","id":"PMC_11599570","title":"Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2.","date":"2001","source":"Cell stress & 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Yi xue ban = Journal of Sichuan University. 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In vitro functional assay linked HSPA1L activity to decidualization.\",\n      \"method\": \"Whole exome sequencing, in vitro chaperone activity biochemical assay of variant proteins, dominant negative assay\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro biochemical assay of multiple variant proteins with mutagenesis-equivalent functional comparison\",\n      \"pmids\": [\"28126021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Melatonin-induced HSPA1L binds to cellular prion protein (PrPC), recruits PrPC to mitochondria, and the HSPA1L-PrPC complex then binds to COX4I (mitochondrial complex IV protein), increasing mitochondrial membrane potential and antioxidant enzyme activity; HSPA1L knockdown blocked these protective effects and abrogated melatonin-mediated rescue of mitophagy in senescent MSCs.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, mitochondrial fractionation, mitochondrial membrane potential assay, ROS/antioxidant assay, murine hindlimb ischemia model\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying protein complex, knockdown with defined molecular and in vivo functional phenotype, multiple orthogonal 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 signaling through AKT/NF-κB and AKT/GSK3β/β-catenin pathways; additionally, HSPA1L is present in the nucleus and directly binds the β-catenin promoter to function as a transcriptional activator, regulating ALDH1 expression and cancer stem cell properties in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), knockdown/overexpression, reporter assays, flow cytometry for ALDH1\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP identifying binding and transcriptional activity, single lab study\",\n      \"pmids\": [\"32971893\"],\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 to clathrin heavy chain and are involved in endocytosis. Overexpression of HSPA1L alleviated organelle stresses (ER stress, autophagy impairment, lysosome dysfunction) in diabetic kidney disease.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, vaspin-/- mouse model, organelle stress assays (ER, lysosome, autophagy markers)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifying complex components, overexpression with defined cellular phenotype, in vivo knockout model\",\n      \"pmids\": [\"33742129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MFG-E8 interacts with HSPA1L (identified by Co-IP), and elevated MFG-E8 downregulates Parkin expression via the HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia; disruption of this pathway by MFG-E8 siRNA rescued mitophagy.\",\n      \"method\": \"Immunoprecipitation, Co-immunoprecipitation, siRNA knockdown, western blotting, in vivo mouse model\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifying interaction, pathway placement by knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"38553831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VEGFR3 binds directly to HSPA1L via its disorder domain (identified by LC-MS/MS and Co-IP), and crotonylation of HSPA1L at K130 by VEGFR3 is required for promoting PARKIN mitochondrial translocation and PARKIN-dependent mitophagy; K130R mutation abolished these protective effects in Ang II-induced proximal tubular cells.\",\n      \"method\": \"LC-MS/MS, Co-immunoprecipitation, site-directed mutagenesis (K130R), in vitro and in vivo (Ang II mouse model) functional assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS identification of interaction and PTM site, mutagenesis validation, in vivo and in vitro orthogonal evidence\",\n      \"pmids\": [\"39875989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A nonsynonymous polymorphism in HSPA1L (M493T, in the peptide-binding domain) in combination with HLA-B*5701 was identified as necessary for abacavir hypersensitivity; abacavir-stimulated monocyte TNF expression was abrogated by CD8+ T cell depletion, indicating an HLA-B*5701-restricted immune mechanism.\",\n      \"method\": \"Fine genetic mapping, haplotype analysis, ex vivo abacavir stimulation with CD8+ T cell depletion, cohort study\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic mapping with ex vivo functional assay; identifies domain relevance (peptide-binding subunit) but no direct biochemical reconstitution of variant function\",\n      \"pmids\": [\"15024131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rare, likely damaging missense variants in HSPA1L were identified in families with recurrent spontaneous preterm birth; in silico analysis predicted an additional phosphorylation site from rs34620296 that could affect chaperone activity or protein stability, and in vitro functional experiments showed a link between HSPA1L activity and decidualization.\",\n      \"method\": \"Whole exome sequencing, in silico phosphorylation prediction, in vitro decidualization functional assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — genetic mapping with limited in vitro functional follow-up; mechanistic link to decidualization not fully characterized\",\n      \"pmids\": [\"30001343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of HSPA1L (either C or T allele of +2437 SNP) in neuroblastoma cells and rat MCAO model reduced neuronal apoptosis under hypoxia/ischemia by upregulating PI3K/p-AKT and downregulating BAX; the T allele showed stronger neuroprotection than the C allele.\",\n      \"method\": \"Lentiviral overexpression, neuronal hypoxic injury model (DFO), rat MCAO model, TTC staining, western blotting for apoptotic proteins\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — overexpression in both in vitro and in vivo models with defined molecular pathway readouts, single lab\",\n      \"pmids\": [\"31170438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hspa1l knockout mice (CRISPR/Cas9) show no defect in spermatogenesis, sperm count, sperm motility, or fertility, and heat stress does not exacerbate testicular apoptosis in Hspa1l-/- mice, demonstrating that HSPA1L is dispensable for physiological spermatogenesis and heat stress responses in the testis.\",\n      \"method\": \"CRISPR/Cas9 knockout, histology, TUNEL assay, sperm motility and count analysis, fertility testing, heat stress challenge\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined phenotypic readouts and heat stress challenge, strong negative result\",\n      \"pmids\": [\"32231871\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPA1L is a constitutively expressed MHC-linked HSP70 family chaperone that localizes to the cytoplasm (and nucleus under heat shock), binds peptides via its C-terminal domain, is phosphorylated by MK2 at Ser241 to enhance chaperone activity under stress, and participates in multiple protein complexes (with PrPC/COX4I at mitochondria, GP78, IGF1Rβ/integrin αV, vaspin/GRP78/clathrin, and VEGFR3) to regulate mitophagy, proteasomal degradation, receptor signaling, and organelle homeostasis, while being dispensable for spermatogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HSPA1L is a constitutively expressed, MHC class III-linked member of the HSP70 chaperone family that functions as a cytoplasmic and stress-responsive nuclear chaperone with roles in protein quality control, mitophagy regulation, and receptor signaling. It binds peptides via its C-terminal substrate-binding domain, is phosphorylated by MK2 at Ser241 to enhance chaperone activity under heat stress, and undergoes crotonylation at K130 by VEGFR3 to promote PARKIN mitochondrial translocation and PARKIN-dependent mitophagy [PMID:11599570, PMID:31642047, PMID:39875989]. HSPA1L modulates protein stability by competitively inhibiting GP78-mediated ubiquitination of PrPC, forms a complex with PrPC and COX4I at mitochondria to sustain mitochondrial membrane potential, and interacts with IGF1Rβ/integrin αV to activate AKT signaling while also directly binding the β-catenin promoter as a transcriptional activator [PMID:28759037, PMID:31965731, PMID:32971893]. Despite high testicular expression, HSPA1L is dispensable for spermatogenesis and testicular heat-stress responses in knockout mice [PMID:32231871].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that HSPA1L is a constitutively expressed, peptide-binding HSP70 family member with regulated subcellular localization answered the basic question of whether this MHC-linked chaperone is functionally active and inducible.\",\n      \"evidence\": \"Peptide-binding assays, immunofluorescence, and expression profiling across human cell lines and tissues\",\n      \"pmids\": [\"11599570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous client proteins not identified\", \"Mechanism of nuclear translocation under heat shock not defined\", \"No comparison of chaperone efficiency relative to HSPA1A/HSPA1B\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic mapping linked the HSPA1L M493T polymorphism in the peptide-binding domain, in combination with HLA-B*5701, to abacavir hypersensitivity, providing the first evidence that HSPA1L peptide-binding variation has immunological consequences.\",\n      \"evidence\": \"Fine genetic mapping, haplotype analysis, and ex vivo abacavir-stimulated TNF assay with CD8+ T cell depletion in patient cohorts\",\n      \"pmids\": [\"15024131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical reconstitution showing how M493T alters peptide presentation\", \"Contribution of HSPA1L versus HLA-B*5701 not individually resolved\", \"No structural basis for altered peptide binding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that HSPA1L binds GP78 and blocks GP78-mediated ubiquitination of PrPC established HSPA1L as a regulator of the ubiquitin-proteasome pathway, linking chaperone activity to protein turnover and tumor progression under hypoxia.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown, ubiquitination assays, and in vivo xenograft in colorectal cancer cells\",\n      \"pmids\": [\"28759037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HSPA1L-GP78 interaction unknown\", \"Whether HSPA1L regulates GP78 activity toward other substrates not tested\", \"Hypoxia-dependent regulation of HSPA1L expression mechanism not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of rare missense HSPA1L variants with decreased or dominant-negative chaperone activity in IBD patients established that HSPA1L functional variation has disease relevance and that its chaperone activity can be quantitatively assessed in vitro.\",\n      \"evidence\": \"Whole exome sequencing of IBD patients with in vitro biochemical chaperone activity assays of purified variant proteins\",\n      \"pmids\": [\"28126021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal relationship between HSPA1L variants and IBD pathogenesis not established\", \"Dominant-negative mechanism not structurally explained\", \"Decidualization link not mechanistically characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of MK2-dependent phosphorylation at Ser241 that enhances chaperone activity defined a stress-activated post-translational regulatory mechanism for HSPA1L, explaining how its activity is tuned during cellular stress.\",\n      \"evidence\": \"Proteomics substrate screen, in vitro kinase assay, Ser241 mutagenesis, chaperone activity assay, and germ cell apoptosis assays\",\n      \"pmids\": [\"31642047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser241 phosphorylation affects client specificity unknown\", \"In vivo relevance of this phosphosite not confirmed in animal models\", \"Dephosphorylation mechanism not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that HSPA1L recruits PrPC to mitochondria and forms a ternary complex with COX4I to enhance mitochondrial function and regulate mitophagy established HSPA1L as a mitochondrial homeostasis factor in mesenchymal stem cells.\",\n      \"evidence\": \"Co-immunoprecipitation, mitochondrial fractionation, membrane potential and ROS assays, siRNA knockdown, and murine hindlimb ischemia model\",\n      \"pmids\": [\"31965731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HSPA1L is directed to mitochondria not defined\", \"Whether the HSPA1L-PrPC-COX4I complex forms in cell types other than MSCs unknown\", \"Melatonin-dependent induction mechanism upstream of HSPA1L not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HSPA1L was shown to interact with IGF1Rβ and integrin αV, activating AKT/NF-κB and AKT/GSK3β/β-catenin signaling, and to directly bind the β-catenin promoter, revealing a dual cytoplasmic–nuclear role in cancer stemness.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, reporter assays, knockdown/overexpression in NSCLC cells\",\n      \"pmids\": [\"32971893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor activity not confirmed by DNA-binding domain mapping\", \"Whether nuclear HSPA1L transcriptional activity is chaperone-dependent unknown\", \"Single-lab finding awaits independent validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR knockout demonstrated that HSPA1L is dispensable for spermatogenesis and testicular heat-stress protection, resolving a long-standing assumption based on its high testicular expression.\",\n      \"evidence\": \"Hspa1l−/− mice generated by CRISPR/Cas9 with histology, TUNEL, sperm analysis, fertility testing, and heat-stress challenge\",\n      \"pmids\": [\"32231871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory upregulation of other HSP70 family members not fully assessed\", \"Phenotypes under non-heat stresses (e.g., oxidative, proteotoxic) not tested\", \"Tissue-specific conditional KO not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of a vaspin–HSPA1L–GRP78–clathrin complex in proximal tubular cells linked HSPA1L to clathrin-mediated endocytosis and organelle stress protection in diabetic kidney disease.\",\n      \"evidence\": \"Co-immunoprecipitation, HSPA1L overexpression, vaspin-knockout mouse model, ER/lysosome/autophagy stress markers\",\n      \"pmids\": [\"33742129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between HSPA1L and clathrin not confirmed by binary assay\", \"How HSPA1L alleviates ER stress mechanistically is not defined\", \"Stoichiometry and stability of the vaspin–HSPA1L–GRP78 complex not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MFG-E8 was shown to interact with HSPA1L and suppress Parkin expression through an HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia, positioning HSPA1L as a node linking extracellular signals to mitophagy regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, western blotting, diabetic sarcopenia mouse model\",\n      \"pmids\": [\"38553831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HSPA1L-MFG-E8 interaction downregulates Parkin is unknown\", \"Whether HSPA1L directly binds Parkin or acts indirectly not resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"VEGFR3-mediated crotonylation of HSPA1L at K130 was shown to be required for PARKIN mitochondrial translocation and mitophagy, establishing a novel post-translational modification that governs HSPA1L's mitophagy-regulatory function.\",\n      \"evidence\": \"LC-MS/MS identification of interaction and K130 crotonylation site, K130R mutagenesis, co-immunoprecipitation, Ang II-induced injury models in vitro and in vivo\",\n      \"pmids\": [\"39875989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme catalyzing K130 crotonylation not identified (VEGFR3 is a kinase, not a known crotonyltransferase)\", \"Whether K130 crotonylation affects chaperone activity per se not tested\", \"Structural basis for crotonylation-dependent PARKIN recruitment unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between HSPA1L's multiple post-translational modifications (Ser241 phosphorylation, K130 crotonylation), its client specificity across cellular contexts, and its apparently redundant role in spermatogenesis remains unintegrated into a unified regulatory model.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of HSPA1L with bound clients or in modified states\", \"Systematic identification of endogenous substrates/clients not performed\", \"Functional redundancy with HSPA1A/HSPA1B not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"HSPA1L-PrPC-COX4I mitochondrial complex\",\n      \"vaspin-HSPA1L-GRP78-clathrin complex\",\n      \"HSPA1L-IGF1Rβ-integrin αV complex\"\n    ],\n    \"partners\": [\n      \"GP78\",\n      \"PRNP\",\n      \"COX4I1\",\n      \"IGF1R\",\n      \"ITGAV\",\n      \"HSPA5\",\n      \"FLT4\",\n      \"MFGE8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}