Affinage

HSPB8

Heat shock protein beta-8 · UniProt Q9UJY1

Length
196 aa
Mass
21.6 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPB8 (HSP22/H11 kinase) is a small heat-shock protein that acts as a molecular chaperone maintaining aggregation-prone substrates in soluble, degradation-competent states (PMID:15879436, PMID:15030316). Its central function is executed within a chaperone-assisted selective autophagy (CASA) module: HSPB8 forms a stable complex with BAG3, and this complex is required for HSPB8-dependent clearance of misfolded substrates such as polyglutamine huntingtin, mutant SOD1, and truncated TDP-43 via macroautophagy (PMID:18006506, PMID:20570967). HSPB8 binds BAG3 through the hydrophobic groove formed by its β4 and β8 strands, which engages two conserved IPV motifs in BAG3; the proline-rich region of BAG3 then recruits the autophagy machinery while the Hsp70-binding BAG domain is dispensable for this activity (PMID:18094623, PMID:19845507). The complex stimulates autophagy non-canonically by inducing eIF2α phosphorylation, a route independent of Hsp70 and of the ER-stress kinase PERK (PMID:19114712), and cooperates to route ubiquitinated cargo into aggresomes, coupling to p62/SQSTM1 and the KEAP1–Nrf2 axis (PMID:29405094). Beyond proteostasis, the HSPB8–BAG3 complex governs actin-based processes during cell division, controlling spindle orientation and chromosome congression as well as contractile-ring disassembly during cytokinesis through actin remodeling and autophagy (PMID:26496431, PMID:28275944). HSPB8 also buffers biomolecular condensates, partitioning into FUS condensates and preventing aberrant liquid-to-solid hardening via α-crystallin-domain-mediated interactions (PMID:34487489). In the heart, HSPB8 drives concentric hypertrophy through Akt/p70-S6K signaling and activates both nuclear and mitochondrial STAT3 functions, translocating to mitochondria via an N-terminal targeting sequence to stimulate oxidative phosphorylation in an iNOS/NO-dependent manner (PMID:12456486, PMID:21747053, PMID:25746286, PMID:22542467). Disease-associated K141 missense mutations reduce chaperone activity, produce aberrantly increased self- and partner interactions, and impair autophagosome–lysosome fusion, while frameshift mutants form insoluble aggregates that sequester CASA components; knock-in versus knock-out mouse comparisons establish a toxic gain-of-function rather than loss-of-function as the primary pathogenic mechanism in HSPB8-associated motor neuropathy and myopathy (PMID:15879436, PMID:16935933, PMID:21985219, PMID:36854646, PMID:28780615).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Established that HSPB8 is not an isolated chaperone but assembles into hetero-oligomeric small-HSP networks, raising the question of which partners and domains define its assemblies.

    Evidence Gel filtration, yeast two-hybrid, cross-linking and FRET of cardiac HSP22 with itself, HSPB7, HSPB2 and HSP27

    PMID:14594798

    Open questions at the time
    • Functional consequence of each hetero-oligomer not defined
    • Stoichiometry in vivo unresolved
  2. 2004 Medium

    Defined the intrinsic biochemical behavior of HSPB8, showing it is an oligomerization-poor, surface-hydrophobic chaperone, distinguishing it mechanistically from canonical sHSPs.

    Evidence In vitro chaperone assays with purified protein (insulin, citrate synthase, ADH, rhodanese), gel filtration, bis-ANS fluorescence, negative kinase assays

    PMID:14985082 PMID:15030316

    Open questions at the time
    • Reconciliation of monomer vs dimer state across studies
    • Physiological substrate spectrum unknown
    • Putative kinase activity not substantiated
  3. 2005 High

    Showed HSPB8 holds misfolded substrates in a soluble, degradation-competent state in cells and localized chaperone activity to the C-terminal domain, with K141 mutations reducing it — first link between sequence, activity, and disease.

    Evidence Co-transfection with Htt43Q, SDS-solubility assays, HSP27-HSPB8 chimeras, missense mutant analysis

    PMID:15879436

    Open questions at the time
    • Degradation route not yet identified
    • Mechanism by which K141 mutation reduces activity unresolved
  4. 2007 High

    Identified the BAG3 partnership as the functional engine of HSPB8 chaperone activity and named macroautophagy as the clearance route, answering how HSPB8 disposes of substrates.

    Evidence Reciprocal co-IP, BAG3 siRNA, BAG3 deletion mutants, LC3-II readout and autophagy inhibitors in cells

    PMID:18006506 PMID:18094623

    Open questions at the time
    • Identity of autophagy receptors not defined
    • How BAG3 proline-rich region engages the machinery unresolved
  5. 2009 High

    Defined the molecular interface (HSPB8 β4/β8 groove binding BAG3 IPV motifs) and an unexpected eIF2α-phosphorylation route to autophagy, mapping both the binding chemistry and the signaling mechanism.

    Evidence Domain mutagenesis of HSPB8 and BAG3 with co-IP and functional Htt43Q assays; eIF2α phosphorylation assays with PERK-independence epistasis

    PMID:19114712 PMID:19845507

    Open questions at the time
    • Kinase responsible for eIF2α phosphorylation not identified
    • Generality across substrate types unresolved
  6. 2010 High

    Extended CASA function to disease-relevant neurodegeneration substrates and established motor-neuron-specific vulnerability and impaired autophagosome-lysosome fusion as consequences of K141 mutation.

    Evidence HSPB8/BAG3/Hsc70/CHIP co-IP with proteasome/autophagy inhibition and G93A-SOD1 mice; primary neuron morphology assays; flow-imaging colocalization of autophagosomes, lysosomes and aggregates

    PMID:20538880 PMID:20570967 PMID:20858900 PMID:21985219

    Open questions at the time
    • Basis for motor-neuron selectivity unknown
    • Loss-of-function vs gain-of-function interpretation not yet resolved at this stage
  7. 2011 Medium

    Resolved the biophysics of the HSPB8-BAG3 complex, showing BAG3 is intrinsically disordered and stabilized by HSPB8, and that K141E weakens binding — connecting mutation to complex integrity.

    Evidence Size-exclusion chromatography, cross-linking, analytical ultracentrifugation, limited proteolysis with purified proteins

    PMID:21767525

    Open questions at the time
    • Functional consequence of variable stoichiometry in cells unresolved
    • Single biophysical study
  8. 2012 High

    Established a cardiac mitochondrial function for HSPB8, showing it stimulates oxidative phosphorylation and reshapes ROS handling through an iNOS/NO-dependent mechanism.

    Evidence Isolated mitochondria from transgenic mice, respiration and superoxide measurements, NOS inhibitor (L-NAME) epistasis

    PMID:22542467

    Open questions at the time
    • Direct mitochondrial substrate/target unknown
    • Link to chaperone activity unclear
  9. 2015 High

    Showed the HSPB8-BAG3 complex moonlights in mitosis to control spindle orientation and chromosome segregation via cortical actin and autophagy, and that mitochondrial translocation of HSPB8 underlies its respiratory effect.

    Evidence siRNA depletion with live imaging and pharmacological rescue (concanavalin A, rapamycin); N20-deletion mutant mitochondrial fractionation and oxygen consumption

    PMID:25746286 PMID:26496431

    Open questions at the time
    • How autophagy controls cortical actin mechanistically unresolved
    • Mitochondrial import pathway not defined
  10. 2017 High

    Demonstrated in vivo that mutant HSPB8 pathology is a toxic gain-of-function and extended the CASA-actin function to cytokinesis.

    Evidence Parallel knock-in and knock-out mouse lines with behavioral, histological and autophagy readouts; siRNA with time-lapse imaging and actin-drug/rapamycin rescue in dividing cells

    PMID:28275944 PMID:28780615

    Open questions at the time
    • Molecular trigger of aggregate toxicity in vivo unresolved
    • Tissue selectivity (nerve vs muscle) mechanism unknown
  11. 2018 Medium

    Defined an aggresome-targeting and KEAP1/Nrf2-coupling role for HSPB8, showing it scaffolds early microaggregate formation and links BAG3 to p62/SQSTM1.

    Evidence siRNA depletion, BAG3-p62 co-IP, KEAP1/Nrf2 pathway analysis, BAG3 mutant rescue

    PMID:29405094

    Open questions at the time
    • Whether HSPB8 directly binds ubiquitinated cargo unresolved
    • Single-lab pathway analysis
  12. 2021 High

    Resolved a condensate-protective function: HSPB8 enters FUS condensates and prevents pathological hardening via α-crystallin-domain interactions specific to the condensate environment, lost in disease mutant.

    Evidence Time-resolved crosslinking mass spectrometry inside condensates, hardening assays, disease-mutant analysis

    PMID:34487489

    Open questions at the time
    • Generality across other condensate-forming proteins unknown
    • Link between condensate buffering and CASA degradation unresolved
  13. 2023 High

    Showed frameshift mutants drive intrinsic C-terminal aggregation that sequesters CASA and autophagy-receptor components, mechanistically explaining proteostasis collapse and muscle phenotypes.

    Evidence Solubility assays, co-IP, filter retardation, CLEM, muscle differentiation assays, molecular dynamics

    PMID:36854646

    Open questions at the time
    • Whether frameshift and K141 mechanisms converge unresolved
    • In vivo validation of sequestration model not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how HSPB8's diverse activities — CASA chaperoning, condensate buffering, cytoskeletal/mitotic regulation, and cardiac mitochondrial/STAT3 signaling — are coordinated within a single protein and which are tissue-restricted.
  • No unifying model linking chaperone and signaling functions
  • Tissue-specific partner usage not systematically mapped
  • Reported phosphorylation sites lack defined upstream regulators in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 3 GO:0005739 mitochondrion 2 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
BAG3CRYABDDX20HSPB1HSPB2HSPB6HSPB7STUB1
Complex memberships
HSPB8-BAG3-HSPA(Hsc70)-STUB1/CHIP CASA complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HspB8 forms a stable complex with BAG3 in cells, and this complex is essential for HspB8 chaperone activity. BAG3 knockdown prevents HspB8-induced degradation of polyglutamine protein Htt43Q, and the complex stimulates macroautophagy as the mechanism for substrate clearance (LC3-II induction, sensitivity to autophagy inhibitors). Co-immunoprecipitation, BAG3 siRNA knockdown, macroautophagy inhibitor treatment, LC3-II western blot The Journal of biological chemistry High 18006506
2007 Within the HspB8-BAG3 complex, the proline-rich region of BAG3 is essential for stimulating clearance of misfolded huntingtin via macroautophagy, whereas the BAG domain (mediating Hsp70/Bcl-2 interaction) is dispensable. HspB8 is proposed to recognize misfolded substrates while BAG3 recruits the autophagy machinery. BAG3 deletion mutants, Htt43Q clearance assay, autophagy reporter assays Autophagy Medium 18094623
2009 HspB8 binds BAG3 through the hydrophobic groove formed by its β4 and β8 strands (the same region responsible for higher-order oligomer formation in other sHSPs). Two conserved IPV (Ile-Pro-Val) motifs in BAG3 mediate binding to HspB8, and deletion of these motifs suppresses HspB8 chaperone activity toward Htt43Q. HspB6 uses the same binding regions to interact with BAG3. Mutagenesis of HspB8 and BAG3 binding domains, co-immunoprecipitation, functional chaperone assay The Biochemical journal High 19845507
2009 HspB8 and BAG3 act non-canonically by inducing phosphorylation of eIF2α, causing translational shut-down and stimulating autophagy. This mechanism is independent of Hsp70 and targets fully folded substrates; it is also independent of the ER stress kinase PERK. eIF2α phosphorylation assays, overexpression/knockdown of HspB8 and BAG3, PERK-independent pathway validation The Journal of biological chemistry High 19114712
2010 Drosophila HSP67Bc is the closest functional ortholog of human HSPB8 and, like HSPB8, induces autophagy via the eIF2α pathway. K141E and K141N mutations of HSPB8 are significantly less efficient than wild-type in decreasing aggregation of mutant ataxin-3 and P182L-HSPB1, supporting loss-of-function as pathogenic mechanism. Drosophila SCA3 eye degeneration model, eIF2α phosphorylation assay, aggregation assays with mutant proteins The Journal of biological chemistry Medium 20858900
2010 HspB8 interacts with the HspB8/BAG3/Hsc70/CHIP multiheteromeric complex in ALS models. HspB8 increases clearance of mutant SOD1 via autophagy even when proteasome activity is blocked, and exerts similar effects on truncated TDP-43. Immunoprecipitation during autophagic flux blockage, pharmacological proteasome and autophagy inhibition, transgenic G93A-SOD1 mouse model Human molecular genetics High 20570967
2005 HspB8 functions as a molecular chaperone in vivo, maintaining misfolded Htt43Q in a soluble state competent for degradation. The C-terminal domain of HspB8 contains the sequence necessary for chaperone activity, and disease-associated K141 missense mutations significantly reduce this activity. Co-transfection with Htt43Q, SDS-solubility assays, proteasome/autophagy inhibitors, Hsp27-HspB8 chimeric proteins, missense mutant analysis Human molecular genetics High 15879436
2003 HSP22 (HSPB8) forms high molecular mass complexes in heart tissue and interacts with itself (N-N and N-C interactions for homodimers), cvHSP (HSPB7) via C-C interaction, and with MKBP (HSPB2) and HSP27. N- and C-terminal domains have distinct binding specificities for different partners. Gel filtration HPLC, yeast two-hybrid, immunoprecipitation, chemical cross-linking, FRET microscopy The Journal of biological chemistry High 14594798
2001 HSP22 was identified as an HSP27-binding protein via yeast two-hybrid screen of a human heart cDNA library using phosphomimetic HSP27 (triple-Asp mutant) as bait. HSP22 interacts preferentially with phosphorylated HSP27. In vitro, HSP22 is phosphorylated by PKC (at Ser14 and Thr63) and p44 MAPK (at Ser27 and Thr87), but not by MAPKAPK-2. Yeast two-hybrid screen, in vitro kinase assays with PKC and MAPK The Journal of biological chemistry Medium 11342557
2004 Human Hsp22 exhibits chaperone-like activity in vitro, preventing DTT-induced aggregation of insulin and thermal aggregation of citrate synthase in a temperature-dependent manner. Hsp22 exists as a monomer in vitro (unlike most sHSPs) with significantly exposed hydrophobic surfaces. In vitro chaperone assay (aggregation prevention), gel filtration, glycerol density-gradient centrifugation, bis-ANS fluorescence The Biochemical journal Medium 15030316
2005 HSP22 interacts with HSP20 and αB-crystallin in addition to previously known partners HSP27, MKBP and cvHSP. In primate cardiac muscle, HSP22 is found in high-molecular-weight complexes containing αB-crystallin and HSP20. Yeast two-hybrid, FRET microscopy, HPLC fractionation of cardiac tissue Biochemical and biophysical research communications Medium 16225851
2006 Disease-associated K141E and K141N mutations in HSP22 cause aberrantly increased interactions with themselves, wild-type HSP22, αB-crystallin, and HSP27, as quantified by FRET and cross-linking. Interaction with HSP20 was not affected by these mutations. Yeast two-hybrid, quantitative FRET in live cells, cross-linking FASEB journal High 16935933
2010 Wild-type HspB8 overexpression in motor neuron-like NSC34 cells promotes co-localization of autophagosomes with lysosomes, while the mutant K141E HspB8 causes autophagosomes to co-localize with protein aggregates but fail to fuse with lysosomes — demonstrating that K141E mutation specifically impairs autophagosome-lysosome delivery. Multispectral imaging flow cytometry autophagy assay, co-localization analysis, patient-derived PBMC analysis Journal of neurochemistry Medium 21985219
2010 Mutant HSPB8 (K141N and K141E) expression in primary motor neurons causes neurite degeneration (reduced neurite number and length, spheroid formation) without inducing apoptosis. This phenotype is absent in sensory neurons, cortical neurons, and glial cells, establishing motor-neuron-specific vulnerability. Primary neuronal and glial cell cultures, morphological neurite analysis, apoptosis assays Human molecular genetics Medium 20538880
2011 Hsp22 knockout mice subjected to pressure overload fail to activate STAT3 target genes, show decreased nuclear STAT3 tyrosine phosphorylation, and have reduced mitochondrial STAT3 translocation and respiration. Hsp22 activates STAT3 via IL-6 production through NF-κB. Hsp22 is therefore a dual activator of nuclear and mitochondrial STAT3 functions. Knockout mouse model, microarray, STAT3 phosphorylation assays, siRNA/overexpression in cardiomyocytes, mitochondrial respiration measurements Circulation High 21747053
2002 Adenoviral overexpression of H11 kinase (HSPB8) in isolated neonatal rat cardiac myocytes induces hypertrophy; cardiac-specific transgenic overexpression produces concentric hypertrophy with preserved function, accompanied by dose-dependent activation of Akt/PKB and p70-S6 kinase, but not the MAP kinase pathway. Adenoviral overexpression in neonatal cardiomyocytes, transgenic mouse model, echocardiography, kinase activity assays Circulation research High 12456486
2007 HspB8 co-localizes and interacts with the 20S proteasome at the nuclear periphery in cardiac hypertrophy. HspB8 overexpression promotes proteasome expression, doubling 20S catalytic activity and causing its redistribution from cytosol to nuclear periphery. Proteasome inhibition reverses HspB8-induced hypertrophy and blocks protein synthesis stimulation. Co-localization and co-immunoprecipitation, proteasome activity assay, subcellular fractionation, proteasome inhibitor treatment (epoxomicin) Cardiovascular research Medium 18006445
2009 H11K (HSPB8) potentiates BMP receptor signaling by increasing association between Alk3 and BMPR-II and their interaction with TAK1. H11K-induced activation of PI3K/Akt is mediated through BMP-receptor-coupled TAK1, and TAK1 inhibition prevents H11K-mediated Akt activation, cardiac growth and survival. Pull-down experiments, phospho-Smad1/5/8 assays, BMP antagonist (noggin) treatment, TAK1 inhibition, adenoviral knockdown Circulation research Medium 19246680
2005 H11 kinase (HSPB8) physically interacts with the α subunit of casein kinase 2 (CK2) and overexpression decreases CK2 kinase activity. High-dose H11 induces apoptosis through kinase-dependent inhibition of CK2, while low-dose H11 induces hypertrophy through kinase-independent Akt activation. Co-immunoprecipitation, CK2 kinase activity assay, kinase-inactive mutant (H11-KI), CK2 inhibitor (DRB) The Biochemical journal Medium 15656793
2004 H11 kinase (HSPB8) interacts with phosphoglucomutase (PGM) as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. H11 kinase overexpression increases PGM Vmax by 20%, increases glycogen content up to 40%, and upregulates GLUT1 at the plasma membrane, promoting glycogen synthesis. Yeast two-hybrid screen, co-immunoprecipitation, enzymatic activity assay, glycogen content measurement, GLUT1 membrane fractionation Molecular and cellular biochemistry Medium 15543936
2006 HSPB8 is identified as a novel TLR4 ligand: recombinant HSPB8 activates monocyte-derived dendritic cells in a TLR4-dependent manner, inducing cytokine production and surface marker upregulation as measured by flow cytometry and multiplex cytokine assays. In vitro DC stimulation with recombinant HSPB8, flow cytometry, multiplex cytokine assay, TLR4-dependence verification Journal of immunology Medium 16709864
2006 HspB8 directly interacts with amyloid-beta peptides (Aβ1-42, Aβ1-40, and Dutch-mutant Aβ1-40) as demonstrated by surface plasmon resonance. Co-incubation of HspB8 with D-Aβ1-40 completely inhibits D-Aβ1-40-mediated cerebrovascular cell death, likely by reducing β-sheet formation and cell surface accumulation. HspB8 does not affect Aβ1-42 β-sheet formation or toxicity. Surface plasmon resonance, β-sheet formation assay (ThT), cerebrovascular cell death assay Acta neuropathologica Medium 16485107
2006 Recombinant HSP22 (HSPB8) directly interrupts CryAB R120G amyloid oligomer formation in vitro. This is confirmed in cardiomyocytes by adenoviral transfection, where HSP22 expression blocks oligomer formation, recovers ubiquitin-proteasomal activity, and restores cellular viability. Recombinant protein co-incubation, native PAGE, anti-oligomer antibody, adenoviral transfection in cardiomyocytes The Journal of biological chemistry Medium 17092938
2010 HspB8 interacts with the DEAD box RNA helicase Ddx20 (gemin3). Disease-associated K141E and K141N mutant forms of HspB8 show abnormally increased binding to Ddx20. RNase treatment partially reduces this interaction, suggesting RNA involvement. Ddx20 connects to SMN protein (mutated in SMA), physically linking HspB8 to SMN-associated motor neuron disease pathways. Yeast two-hybrid screen, co-immunoprecipitation, chemical cross-linking, quantitative FRET in live cells, RNase treatment Cell stress & chaperones Medium 20157854
2011 Phosphorylation of HspB8 by ERK1 kinase occurs at Ser24 and Thr87 in vitro (with T87 being the dominant site). Phosphomimicking mutations at these sites alter intrinsic fluorescence, susceptibility to proteolysis, and concentration-dependent association of HspB8 subunits. Phosphorylation at S24 and S27 decreases, while T87 increases, chaperone-like activity. In vitro ERK1 kinase assay with phosphomimicking mutants, intrinsic fluorescence, chymotrypsinolysis, analytical ultracentrifugation, chaperone activity assay Molecular and cellular biochemistry Medium 21526341
2008 Phosphorylation of HspB8 by cAMP-dependent protein kinase (PKA) occurs primarily at Ser57 in vitro. Phosphorylation/phosphomimicking mutations at Ser57 (or Ser24/Ser57) alter tryptophan environment, increase chymotrypsinolysis susceptibility, and decrease chaperone-like activity toward insulin and rhodanese substrates. In vitro PKA kinase assay, phosphomimicking mutants, CD spectroscopy, chymotrypsinolysis, chaperone activity assay Biochemistry (Biokhimiia) Medium 18298377
2015 The BAG3-HSPB8 complex regulates spindle orientation and chromosome segregation during mitosis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. Depletion of BAG3 causes metaphase plate congression defects in an HSPB8-dependent manner, with actin retraction fiber disorganization and abnormal spindle rotation. These phenotypes are rescued by cortex-rigidity restoration (concanavalin A) and rapamycin (autophagy promotion), but mimicked by lysosomal inhibitors. siRNA depletion of BAG3 and HSPB8, live cell imaging, spindle orientation assay, actin visualization, pharmacological rescue experiments PLoS genetics High 26496431
2017 The HSPB8-BAG3 complex is required for accurate actin-based contractile ring disassembly during cytokinesis. HSPB8 silencing decreases mitotic BAG3 levels, delays cytokinesis, causes F-actin accumulation at the intercellular bridge, and increases bi/multinucleation. These defects are rescued by actin-sequestering drug latrunculin A, branched-actin inhibitor CK666, or rapamycin, and mimicked by lysosomal inhibition. siRNA silencing, time-lapse imaging, F-actin quantification, pharmacological rescue (latrunculin A, CK666, rapamycin), lysosomal inhibition Cell stress & chaperones High 28275944
2018 HSPB8 cooperates with BAG3 to promote aggresome targeting of ubiquitinated proteins upon proteasome inhibition. HSPB8 depletion impairs early ubiquitinated microaggregate formation and reduces BAG3 coupling to p62/SQSTM1, hindering KEAP1 sequestration and Nrf2 stabilization. Aggresome targeting can be restored in BAG3-depleted cells by a BAG3 mutant defective in HSPB8 binding, uncoupling HSPB8 from BAG3 for aggresome function. siRNA depletion, co-immunoprecipitation of BAG3-p62 complex, KEAP1/Nrf2 pathway analysis, mutant BAG3 rescue experiments FASEB journal Medium 29405094
2011 In vitro biochemical analysis shows that wild-type HspB8 forms tight complexes with BAG3. K141E mutant HspB8 and HspB6 bind BAG3 more weakly. The stoichiometry of HspB8-BAG3 complexes is variable and concentration-dependent. Bag3 is intrinsically disordered and interaction with HspB8 increases thermal stability and protease resistance of the complex. Size-exclusion chromatography, chemical cross-linking, analytical ultracentrifugation, intrinsic fluorescence, limited proteolysis Archives of biochemistry and biophysics Medium 21767525
2015 Translocation of Hsp22 to mitochondria (via its N-terminal 20 amino acid mitochondrial localization sequence) is required for stimulation of oxidative phosphorylation. A deletion mutant lacking this sequence (N20-Hsp22) neither translocates to mitochondria nor stimulates respiration, and also fails to promote iNOS mitochondrial localization, despite increasing global iNOS expression. Adenoviral WT and N20 deletion mutant, mitochondrial fractionation, oxygen consumption rate measurement, iNOS localization PloS one High 25746286
2012 Hsp22 overexpression in transgenic mice increases mitochondrial NO production (via iNOS) and stimulates oxidative phosphorylation, while decreasing maximal superoxide production by complexes I and III and inhibiting reverse electron flow. After anoxia, mitochondria from transgenic mice show reduced oxidative phosphorylation and H2O2 production. L-NAME (NOS inhibitor) abolishes these effects, establishing an NO-dependent mechanism. Isolated mitochondria from transgenic mice, oxygen consumption, superoxide measurement, NO production assay, NOS inhibitor treatment Free radical biology & medicine High 22542467
2006 H11/HspB8 overload in melanoma cells induces apoptosis through physical complexation with TAK1 and activation of TAK1 and p38 MAPK. The W51C mutant of H11/HspB8, which has dominant anti-apoptotic activity, does not bind or activate TAK1. TAK1-mediated β-catenin phosphorylation inhibits nuclear accumulation of β-catenin and downstream transcription factors. Dominant-negative TAK1 (K63W) inhibits β-catenin phosphorylation and caspase activation. Co-immunoprecipitation (H11/HspB8-TAK1), kinase activity assays, dominant-negative TAK1 mutant, caspase and TUNEL assays Oncogene Medium 17173073
2021 HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening (aberrant liquid-to-solid transition) through interactions mediated by its α-crystallin domain (αCD) that are specific to the condensate environment. The αCD-mediated interactions are altered in a disease-associated HspB8 mutant, abrogating its ability to prevent FUS condensate hardening. Misfolding of the RNA recognition motif of FUS drives condensate aging. Quantitative time-resolved crosslinking mass spectrometry inside condensates, condensate hardening assays, disease mutant analysis eLife High 34487489
2023 HSPB8 frameshift (fs) mutants form highly insoluble cytoplasmic aggregates and sequester CASA complex members (HSPA/BAG3/STUB1) and autophagy receptors (SQSTM1/p62, TAX1BP1) into these aggregates, causing a general failure in proteostasis and CASA capability. Aggregation is intrinsic to the mutated C-terminal sequence and occurs independently of CASA member interactions. HSPB8_fs mutants impair muscle cell differentiation and sarcomere organization. Biochemical solubility assays, co-immunoprecipitation, filter retardation assay, CLEM, muscle differentiation assays, molecular dynamics Autophagy High 36854646
2017 Homozygous knock-in mice expressing mutant Hspb8 develop motor deficits with peripheral nerve degeneration and severe muscle atrophy, Z-disk disorganization, and Hspb8/αB-crystallin/desmin aggregates correlating with reduced autophagy markers. Homozygous knock-out mice show normal locomotor performance, indicating toxic gain-of-function of mutant Hspb8 as the primary pathogenic mechanism rather than loss-of-function. Knock-in/knock-out mouse model, behavioral assays, histopathology, autophagy marker analysis, immunofluorescence of protein aggregates Acta neuropathologica High 28780615
2004 Human Hsp22 forms stable dimers in solution (not higher oligomers like most sHSPs). It is highly susceptible to oxidation, forming disulfide-crosslinked dimers and high-molecular-mass oligomers upon oxidation, accompanied by loss of secondary and tertiary structure. Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and rhodanese, but has negligibly low autophosphorylation and cannot phosphorylate casein or histone in vitro. Size exclusion chromatography, cross-linking, CD spectroscopy, in vitro chaperone assay, in vitro kinase assay Biochemical and biophysical research communications Medium 14985082
2007 Hsp22 (HSPB8) localizes to the plasma membrane in human neuroblastoma SK-N-SH cells. Purified Hsp22 interacts with lipid vesicles, with stronger binding to phosphatidic acid, phosphatidylinositol, or phosphatidylserine-containing vesicles than phosphatidylcholine vesicles. Membrane binding causes conformational changes in Hsp22. Confocal immunolocalization, tryptophan fluorescence quenching, time-resolved fluorescence, gel filtration chromatography with lipid vesicles, CD spectroscopy The Biochemical journal Medium 17020537
2011 Hsp22 knockdown in U87 glioblastoma cells increases Sam68 mRNA and protein levels, indicating Hsp22 negatively regulates Sam68 expression. Hsp22 knockdown also alters cell morphology, enhances proliferation, decreases G0/G1 fraction, and increases cyclin E, cyclin A, RNR, and PCNA, suggesting Hsp22 limits G1-to-S phase transition. siRNA knockdown, RT-PCR, western blot, cell cycle analysis by flow cytometry Journal of cellular physiology Low 21678403
2013 The α-crystallin domain of Hspb8 (truncated form) is sufficient to promote survival and differentiation of adult hippocampal neural precursor cells both in vitro and in vivo. Lentiviral overexpression of Hspb8 in adult mouse dentate gyrus doubles surviving cells and promotes neurogenesis. Hspb8 increases Akt phosphorylation in precursor cells, suggesting a cell-autonomous prosurvival mechanism. Lentiviral overexpression in vivo (mouse dentate gyrus), gain/loss-of-function in vitro, domain truncation experiments, Akt phosphorylation assay The Journal of neuroscience Medium 23536091
2017 HSP22 (HSPB8) co-immunoprecipitates with PI3K (but not AKT) in HCC-derived HuH-7 cells. HSP22 knockdown markedly enhances AKT phosphorylation induced by TGF-α or HGF, and PI3K/AKT inhibitors suppress the migration amplification caused by HSP22 knockdown, indicating that HSP22 suppresses cell migration via interaction with and downregulation of PI3K signaling. Co-immunoprecipitation (HSP22-PI3K), siRNA knockdown, phospho-AKT western blot, migration assay, pharmacological inhibitors Biochimica et biophysica acta. Molecular basis of disease Medium 28456666

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1986 Translational and transcriptional control elements in the untranslated leader of the heat-shock gene hsp22. Cell 406 3943132
2007 HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. The Journal of biological chemistry 300 18006506
2010 The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Human molecular genetics 288 20570967
2004 Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 255 14734639
2012 Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology 231 22521623
2006 Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 227 16709864
2007 HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy 206 18094623
2009 Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction. The Biochemical journal 160 19845507
2005 HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Human molecular genetics 144 15879436
2003 Interaction of human HSP22 (HSPB8) with other small heat shock proteins. The Journal of biological chemistry 116 14594798
2004 Decreased lifespan in the absence of expression of the mitochondrial small heat shock protein Hsp22 in Drosophila. The Journal of biological chemistry 114 15331597
2001 HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27). The Journal of biological chemistry 112 11342557
2006 Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity. Acta neuropathologica 110 16485107
2015 Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology 108 26718575
2008 HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{alpha} phosphorylation. The Journal of biological chemistry 103 19114712
2004 Mammalian Hsp22 is a heat-inducible small heat-shock protein with chaperone-like activity. The Biochemical journal 102 15030316
2011 H11 kinase/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac overload. Circulation 100 21747053
2001 Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9. Biochimica et biophysica acta 98 11470154
1999 Aging-specific expression of Drosophila hsp22. Developmental biology 93 10049568
2009 Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy. PloS one 92 19399179
2002 H11 kinase is a novel mediator of myocardial hypertrophy in vivo. Circulation research 81 12456486
2010 Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases. The Journal of biological chemistry 78 20858900
2010 Mutant HSPB8 causes motor neuron-specific neurite degeneration. Human molecular genetics 77 20538880
2000 Increased hsp22 RNA levels in Drosophila lines genetically selected for increased longevity. The journals of gerontology. Series A, Biological sciences and medical sciences 76 11078089
2005 Interactions of HSP22 (HSPB8) with HSP20, alphaB-crystallin, and HSPB3. Biochemical and biophysical research communications 75 16225851
2003 Expression of small heat shock proteins HspB2, HspB8, Hsp20 and cvHsp in different tissues of the perinatal developing pig. European journal of cell biology 73 14629120
2006 Abnormal small heat shock protein interactions involving neuropathy-associated HSP22 (HSPB8) mutants. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 16935933
2021 HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain. eLife 68 34487489
2000 The small heat shock protein Hsp22 of Drosophila melanogaster is a mitochondrial protein displaying oligomeric organization. The Journal of biological chemistry 68 10896659
2017 A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8. Acta neuropathologica 63 28780615
2017 The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases. Frontiers in molecular neuroscience 62 28680390
2009 Expression of hsp22 and hsp70 transgenes is partially predictive of drosophila survival under normal and stress conditions. The journals of gerontology. Series A, Biological sciences and medical sciences 61 19420297
2010 Knocking down expression of Hsp22 and Hsp23 by RNA interference affects recovery from chill coma in Drosophila melanogaster. The Journal of experimental biology 59 21112994
2006 Interruption of CryAB-amyloid oligomer formation by HSP22. The Journal of biological chemistry 58 17092938
2015 A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis. PLoS genetics 54 26496431
2011 HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. Journal of the peripheral nervous system : JPNS 54 22176143
2019 HSP22 suppresses diabetes-induced endothelial injury by inhibiting mitochondrial reactive oxygen species formation. Redox biology 52 30640127
2013 Protein interactomes of three stress inducible small heat shock proteins: HspB1, HspB5 and HspB8. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 52 23697380
2004 Some properties of human small heat shock protein Hsp22 (H11 or HspB8). Biochemical and biophysical research communications 52 14985082
2018 HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 50 29405094
2021 The Role of HSPB8, a Component of the Chaperone-Assisted Selective Autophagy Machinery, in Cancer. Cells 49 33562660
2007 Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor-positive breast cancer cells. Cell stress & chaperones 48 18229450
2011 HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes. Journal of neurochemistry 47 21985219
2007 Proteasome activation during cardiac hypertrophy by the chaperone H11 Kinase/Hsp22. Cardiovascular research 47 18006445
2011 Biochemical characterization of small heat shock protein HspB8 (Hsp22)-Bag3 interaction. Archives of biochemistry and biophysics 46 21767525
2008 Structure, properties, and functions of the human small heat-shock protein HSP22 (HspB8, H11, E2IG1): a critical review. Journal of neuroscience research 46 17722063
2009 Activation of the bone morphogenetic protein receptor by H11kinase/Hsp22 promotes cardiac cell growth and survival. Circulation research 45 19246680
1995 Sequence and expression of the mRNA encoding HSP22, the mitochondrial small heat-shock protein in pea leaves. The Biochemical journal 45 7487935
2017 The small heat shock protein B8 (HSPB8) modulates proliferation and migration of breast cancer cells. Oncotarget 43 28060751
2007 Interaction of mammalian Hsp22 with lipid membranes. The Biochemical journal 41 17020537
2017 Tat-HSP22 inhibits oxidative stress-induced hippocampal neuronal cell death by regulation of the mitochondrial pathway. Molecular brain 40 28052764
2004 Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression. Acta biochimica et biophysica Sinica 40 15346199
2018 HSPB8 over-expression prevents disruption of blood-brain barrier by promoting autophagic flux after cerebral ischemia/reperfusion injury. Journal of neurochemistry 39 30422312
2013 A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L. Neuromuscular disorders : NMD 39 23796487
2014 The small heat shock protein B8 (HSPB8) confers resistance to bortezomib by promoting autophagic removal of misfolded proteins in multiple myeloma cells. Oncotarget 38 25051369
2004 A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Human genetics 38 15021985
2005 H11 has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes. The Biochemical journal 37 15656793
2006 Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, H11) that is expressed in human neuromuscular disorders. Archives of biochemistry and biophysics 36 16949546
2018 Heat Shock Protein B8 (HSPB8) Reduces Oxygen-Glucose Deprivation/Reperfusion Injury via the Induction of Mitophagy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 30071537
2017 Fine-tuning of actin dynamics by the HSPB8-BAG3 chaperone complex facilitates cytokinesis and contributes to its impact on cell division. Cell stress & chaperones 35 28275944
2015 Drosophila melanogaster Hsp22: a mitochondrial small heat shock protein influencing the aging process. Frontiers in genetics 35 25852752
2011 Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells. Journal of cellular physiology 35 21678403
2009 Thermally induced structural changes of intrinsically disordered small heat shock protein Hsp22. Biophysical chemistry 35 19783089
2010 Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms with the RNA helicase Ddx20 (gemin3). Cell stress & chaperones 34 20157854
2001 In vivo modifications of the maize mitochondrial small heat stress protein, HSP22. The Journal of biological chemistry 34 11397800
2015 Drosophila melanogaster mitochondrial Hsp22: a role in resistance to oxidative stress, aging and the mitochondrial unfolding protein response. Biogerontology 33 26155908
2011 Vaccination of goats with DNA vaccines encoding H11 and IL-2 induces partial protection against Haemonchus contortus infection. Veterinary journal (London, England : 1997) 33 21330170
2007 Effect of mutations in the beta5-beta7 loop on the structure and properties of human small heat shock protein HSP22 (HspB8, H11). The FEBS journal 33 17922839
2017 Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy. European journal of neurology 32 29029362
2015 Regulation by heat shock protein 22 (HSPB8) of transforming growth factor-α-induced ovary cancer cell migration. Archives of biochemistry and biophysics 32 25731856
2012 Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients. Neuromuscular disorders : NMD 32 22595202
2017 Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Biochimica et biophysica acta. Molecular basis of disease 31 28456666
2018 Exploring the multifaceted roles of heat shock protein B8 (HSPB8) in diseases. European journal of cell biology 30 29555102
2016 Virulence Gene Profiles and Clonal Relationships of Escherichia coli O26:H11 Isolates from Feedlot Cattle as Determined by Whole-Genome Sequencing. Applied and environmental microbiology 30 27107118
2007 Therapeutic potential of H11 kinase for the ischemic heart. Cardiovascular drug reviews 30 17445085
2006 Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1. Oncogene 30 17173073
2021 Hsp22 ameliorates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidative stress, and apoptosis. Bioengineered 29 34839787
2019 New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy. Neurology. Genetics 29 31403083
2018 Alkaline and Halophilic Protease Production by Bacillus luteus H11 and Its Potential Industrial Applications. Food technology and biotechnology 27 30923452
2013 The α crystallin domain of small heat shock protein b8 (Hspb8) acts as survival and differentiation factor in adult hippocampal neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 23536091
2004 Doxycycline-regulated over-expression of hsp22 has negative effects on stress resistance and life span in adult Drosophila melanogaster. Mechanisms of ageing and development 27 15491684
2017 HSPB8 Promotes the Fusion of Autophagosome and Lysosome during Autophagy in Diabetic Neurons. International journal of medical sciences 25 29200947
2023 HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies. Autophagy 24 36854646
2016 HspB8 mediates neuroprotection against OGD/R in N2A cells through the phosphoinositide 3-kinase/Akt pathway. Brain research 23 27178361
2012 Cardiac H11 kinase/Hsp22 stimulates oxidative phosphorylation and modulates mitochondrial reactive oxygen species production: Involvement of a nitric oxide-dependent mechanism. Free radical biology & medicine 23 22542467
2011 Preemptive conditioning of the swine heart by H11 kinase/Hsp22 provides cardiac protection through inducible nitric oxide synthase. American journal of physiology. Heart and circulatory physiology 23 21317305
2009 The involvement of HSP22 from bay scallop Argopecten irradians in response to heavy metal stress. Molecular biology reports 23 19585273
2017 L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways. Frontiers in neuroscience 22 28747872
2020 HSPB8 overexpression prevents disruption of blood-brain barrier after intracerebral hemorrhage in rats through Akt/GSK3β/β-catenin signaling pathway. Aging 21 32889520
2015 Heat shock protein 22 (Hsp22) regulates oxidative phosphorylation upon its mitochondrial translocation with the inducible nitric oxide synthase in mammalian heart. PloS one 21 25746286
2011 Phosphorylation of human small heat shock protein HspB8 (Hsp22) by ERK1 protein kinase. Molecular and cellular biochemistry 21 21526341
2012 Restored expression of the atypical heat shock protein H11/HspB8 inhibits the growth of genetically diverse melanoma tumors through activation of novel TAK1-dependent death pathways. Cell death & disease 20 22898869
2004 Increased expression of H11 kinase stimulates glycogen synthesis in the heart. Molecular and cellular biochemistry 20 15543936
2022 H11-induced immunoprotection is predominantly linked to N-glycan moieties during Haemonchus contortus infection. Frontiers in immunology 19 36405717
2019 Hsp22 overexpression induces myocardial hypertrophy, senescence and reduced life span through enhanced oxidative stress. Free radical biology & medicine 19 31047988
2011 The Levels of H11/HspB8 DNA methylation in human melanoma tissues and xenografts are a critical molecular marker for 5-Aza-2'-deoxycytidine therapy. Cancer investigation 19 21649464
2016 Changes in Drosophila mitochondrial proteins following chaperone-mediated lifespan extension confirm a role of Hsp22 in mitochondrial UPR and reveal a mitochondrial localization for cathepsin D. Mechanisms of ageing and development 18 26930296
2008 Phosphorylation by cyclic AMP-dependent protein kinase inhibits chaperone-like activity of human HSP22 in vitro. Biochemistry. Biokhimiia 18 18298377
2007 Haemonchus contortus: characterization of the baculovirus expressed form of aminopeptidase H11. Experimental parasitology 18 17482594
2005 Histone acetylation regulates both transcription initiation and elongation of hsp22 gene in Drosophila. Biochemical and biophysical research communications 18 15607742

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