Affinage

HSPA1L

Heat shock 70 kDa protein 1-like · UniProt P34931

Length
641 aa
Mass
70.4 kDa
Annotated
2026-06-10
39 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 Medium

    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

    PMID:11599570

    Open questions at the time
    • No substrate specificity defined beyond model peptides
    • Nuclear function after heat-shock translocation not defined
  2. 2004 Medium

    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

    PMID:15024131

    Open questions at the time
    • Direct biochemical mechanism of HSPA1L in antigen presentation not demonstrated
    • Genetic association does not isolate HSPA1L function from HLA context
  3. 2017 High

    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

    PMID:28759037

    Open questions at the time
    • Whether HSPA1L sequesters GP78 or PrPC directly not resolved
    • Generality beyond hypoxic colorectal cancer untested
  4. 2019 High

    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

    PMID:31642047

    Open questions at the time
    • In vivo relevance to spermatogenesis not established (contrasts with KO phenotype)
    • Structural basis for activity enhancement unknown
  5. 2020 Medium

    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

    PMID:31965731

    Open questions at the time
    • Direct COX4IA binding by HSPA1L vs PrPC not separated
    • Single-lab Co-IP without reciprocal validation
  6. 2020 Medium

    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

    PMID:32971893

    Open questions at the time
    • Sequence-specific DNA binding by a chaperone not biochemically reconciled
    • Direct vs indirect promoter occupancy unresolved
  7. 2020 High

    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

    PMID:32231871

    Open questions at the time
    • Redundant paralog(s) compensating not identified
    • Phenotypes outside testis not assessed
  8. 2021 Medium

    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

    PMID:33742129

    Open questions at the time
    • Direct clathrin binding by HSPA1L not isolated from complex partners
    • Mechanism connecting endocytosis to organelle protection unclear
  9. 2021 Medium

    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

    PMID:33679887

    Open questions at the time
    • Functional consequence of elevated HSPA1L in COVID-19 not determined
    • Correlative methylation-expression link in patient samples
  10. 2024 Medium

    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

    PMID:38553831

    Open questions at the time
    • How HSPA1L controls Parkin levels mechanistically unknown
    • Single-lab Co-IP without orthogonal interaction validation
  11. 2025 High

    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

    PMID:39875989

    Open questions at the time
    • Crotonyltransferase responsible not identified
    • How K130 crotonylation alters HSPA1L-PARKIN interaction unresolved
  12. 2026 Medium

    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

    PMID:42072126

    Open questions at the time
    • Direct chaperone stabilization of GPX4 not shown by reconstitution
    • Whether the effect requires chaperone activity not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
FLT4GP78HSPA5IGF1RITGAVMFGE8PRNPVASN

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Peptide binding assay, immunolocalization/subcellular fractionation, RNA expression profiling in human tissues and cell lines, western blot Cell stress & chaperones Medium 11599570
2004 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. Fine recombinant genetic mapping, haplotype analysis, ex vivo abacavir stimulation with CD8+ T cell depletion and monocyte TNF measurement Proceedings of the National Academy of Sciences of the United States of America Medium 15024131
2014 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. In vitro chaperone activity biochemical assay of variant proteins; dominant-negative assessment Genome medicine High 28126021
2017 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. Co-immunoprecipitation, HSPA1L knockdown, in vivo tumor model, ubiquitination assay Oncogene High 28759037
2019 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. Proteomics-based substrate screen, in vitro kinase assay with site-directed mutagenesis (Ser241), chaperone activity assay, cell apoptosis assay under heat stress Cell stress & chaperones High 31642047
2020 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. Co-immunoprecipitation, HSPA1L knockdown, mitochondrial fractionation, mitochondrial membrane potential measurement, murine hindlimb ischemia model Aging cell Medium 31965731
2020 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. Co-immunoprecipitation, chromatin immunoprecipitation (promoter binding), HSPA1L overexpression/knockdown, signaling pathway analysis International journal of molecular sciences Medium 32971893
2020 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. CRISPR/Cas9 knockout, histological staining, immunofluorescence, TUNEL assay, sperm motility/count measurement, fertility testing, heat stress treatment PeerJ High 32231871
2021 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. Co-immunoprecipitation, HSPA1L overexpression, organelle stress assays (ER stress, autophagy, lysosome), in vivo vaspin-/- obese mouse model Communications biology Medium 33742129
2021 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. Promoter methylation analysis (bisulfite sequencing/pyrosequencing), mRNA quantification in patient blood, in vitro SARS-CoV-2 infection model, AZA (demethylating agent) treatment comparison Frontiers in genetics Medium 33679887
2024 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. Immunoprecipitation, co-immunoprecipitation, MFG-E8 overexpression/siRNA, western blot for Parkin/PINK1/LC3B/P62 Journal of cachexia, sarcopenia and muscle Medium 38553831
2025 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. LC-MS/MS, co-immunoprecipitation, site-directed mutagenesis (K130R), PARKIN mitochondrial translocation assay, in vivo and in vitro Ang II models Cell communication and signaling : CCS High 39875989
2026 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. LiP-MS (limited proteolysis mass spectrometry), molecular dynamics simulation, transcriptomics, metabolomics, HSPA1L expression modulation, GPX4 stability assay in HaCaT cells and 3D skin organoids Antioxidants (Basel, Switzerland) Medium 42072126
2018 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. In vitro decidualization assay with HSPA1L activity modulation; whole exome sequencing; in silico phosphorylation prediction PLoS genetics Low 30001343
2019 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. 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 Gene Medium 31170438

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proceedings of the National Academy of Sciences of the United States of America 336 15024131
1993 Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). Scandinavian journal of immunology 109 7901896
2020 Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway. Aging cell 76 31965731
2003 Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations and interfere with outcome after major injury. Critical care medicine 62 12544996
2005 HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease. Transplantation 40 15818324
2018 Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth. PLoS genetics 38 30001343
2016 Modification of embryonic resistance to heat shock in cattle by melatonin and genetic variation in HSPA1L. Journal of dairy science 37 27614828
2021 SARS-CoV-2 Infection-Induced Promoter Hypomethylation as an Epigenetic Modulator of Heat Shock Protein A1L (HSPA1L) Gene. Frontiers in genetics 36 33679887
2017 Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis. Oncogene 35 28759037
2001 Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2. Cell stress & chaperones 32 11599570
2006 HSP70-hom gene single nucleotide (+2763 G/A and +2437 C/T) polymorphisms in sarcoidosis. International journal of immunogenetics 31 16611259
2009 TNF, LTA, HSPA1L and HLA-DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole. Pharmacogenomics 30 19374512
2005 Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia. Neuroscience research 30 15963589
2017 De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease. Genome medicine 23 28126021
2000 A novel variant of the MHC-linked hsp70, hsp70-hom, is associated with rheumatoid arthritis. Tissue antigens 21 10958354
1994 HSP70-Hom NcoI polymorphism and HLA-associations in the Finnish population and in patients with ankylosing spondylitis or reactive arthritis. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 20 9098422
2024 The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol. Journal of cachexia, sarcopenia and muscle 19 38553831
2021 A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. Communications biology 18 33742129
2020 The heat shock protein family gene Hspa1l in male mice is dispensable for fertility. PeerJ 18 32231871
2020 HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rβ and Regulating β-Catenin Transcription. International journal of molecular sciences 16 32971893
2017 Polymorphisms of heat shock protein 70 genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility of noise-induced hearing loss in a Chinese population: A case-control study. PloS one 13 28182740
2012 Association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with COPD in Croatian population. Clinical biochemistry 12 22542718
2019 MAPKAP kinase 2-mediated phosphorylation of HspA1L protects male germ cells from heat stress-induced apoptosis. Cell stress & chaperones 10 31642047
2010 Synergistic effect and VEGF/HSP70-hom haplotype analysis: relationship to prostate cancer risk and clinical outcome. Human immunology 10 20096741
2019 HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with idiopathic male infertility in Iranian population. European journal of obstetrics, gynecology, and reproductive biology 9 31228677
2007 Association of HSP70-hom genetic variant with prostate cancer risk. Molecular biology reports 9 17578680
2019 The differential neuroprotection of HSP70-hom gene single nucleotide polymorphisms: In vitro (neuronal hypoxic injury model) and in vivo (rat MCAO model) studies. Gene 6 31170438
2018 Association Studies of HSPA1A and HSPA1L Gene Polymorphisms With Schizophrenia. Archives of medical research 6 30342847
2015 Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case-control study. PloS one 6 25789467
2025 VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L. Cell communication and signaling : CCS 5 39875989
2015 Genetic polymorphisms of hspa1b and hspa1l in infertile men. JPMA. The Journal of the Pakistan Medical Association 5 26160076
2006 Polymorphisms of heat shock protein-70 (HSPA1B and HSPA1L loci) do not influence infection or outcome risk in critically ill surgical patients. Shock (Augusta, Ga.) 5 16525348
2015 Elevated level of HSPA1L mRNA correlates with graft-versus-host disease. Transplant immunology 4 25680846
2014 HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance. Environmental and molecular mutagenesis 4 25044062
2010 Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation. Clinical transplantation 3 19758266
2026 Evaluating the Effect of RNA Interference of Two Heat Shock Proteins (HSPA1L, HSP90B1) in Inducing Apoptosis in Acyrthosiphon Pisum. Biochemistry & molecular biology journal 0 42039770
2026 Hesperidin from Chenpi Ameliorates Skin Photoaging by Targeting HSPA1L to Stabilize GPX4 and Suppress Ferroptosis. Antioxidants (Basel, Switzerland) 0 42072126
2020 HSPA1L rs1061581 polymorphism is associated with the risk of preeclampsia in Han Chinese women. Bioscience reports 0 32039449
2016 [Interaction Between Occupational Vanadium Exposure and hsp70-hom on Neurobehavioral Function]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 27062781

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