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Gene Review

HSPB8  -  heat shock 22kDa protein 8

Homo sapiens

Synonyms: Alpha-crystallin C chain, CMT2L, CRYAC, DHMN2, E2-induced gene 1 protein, ...
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Disease relevance of HSPB8


High impact information on HSPB8

  • Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1 [7].
  • Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates [7].
  • In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22) [7].
  • In addition, one clone (37-11) expresses a human muscle-specific surface antigen (5.1 H11) and, under appropriate conditions, can be induced to form myotubes [8].
  • In the present study, we investigated the capacity of the sHsp, HspB8/Hsp22, to prevent protein aggregation in the cells using the polyglutamine protein Htt43Q as a model [9].

Chemical compound and disease context of HSPB8


Biological context of HSPB8

  • Using yeast two-hybrid assays and Förster resonance energy transfer microscopy, we now show that HSP22 also can interact with two additional members of the sHSP family, alphaB-crystallin and HSP20 [11].
  • In contrast, however, with Abeta(1-42), HspB8 neither affected beta-sheet formation nor Abeta-mediated cell death [2].
  • Here, we report a novel c.423G-->T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II [12].
  • It was abrogated by co-treatment with both inhibitors, suggesting that H11-triggered apoptosis is both caspase- and p38MAPK-dependent [5].
  • Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells [5].

Anatomical context of HSPB8


Associations of HSPB8 with chemical compounds

  • Forced H11 expression by Aza-C treatment, transient transfection with H11 expression vectors, or retrovirus-mediated delivery of H11 under the control of a tetracycline-sensitive promoter triggered apoptosis [5].
  • One such mutation at a highly conserved arginine residue was shown to cause major conformational defects and intracellular aggregation of alphaA- and alphaB-crystallins and HspB8 [17].
  • Size exclusion chromatography and chemical crosslinking with dimethylsuberimidate indicate that Hsp22 forms stable dimers [18].
  • Mass spectrometric analyses were performed on detergent extracts of homogenized adult H. contortus and on purified H11, a glycoprotein isolated from intestinal brush borders which has been previously shown to be an effective vaccine antigen [19].
  • In the light of a hMR-LBD model based on the structure of the progesterone-associated receptor-LBD, we propose that the integrity of the H11-H12 loop is crucial for folding the receptor into a ligand-binding competent state and for establishing the network of contacts that stabilize the active receptor conformation [20].

Physical interactions of HSPB8

  • This interaction results in disruption of the ER/Sp1 complex and inhibition of E2-induced gene expression [21].

Enzymatic interactions of HSPB8

  • Hsp22 possesses a negligibly low autophosphorylation activity and under the conditions used is unable to phosphorylate casein or histone [18].

Regulatory relationships of HSPB8

  • Using flow cytometry and multiplex cytokine assays, we showed that both alphaA crystallin and HSPB8 were able to activate DCs and that this activation was TLR4 dependent [1].
  • Furthermore, Western blot and immunohistochemistry showed that HSPB8 was abundantly expressed in synovial tissue from patients with RA [1].
  • We conclude that HspB8 might play an important role in regulating Abeta aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D [2].

Other interactions of HSPB8

  • In this review, we will summarize the current knowledge of small HSPs, in particular HSPB1 and HSPB8, and discuss their role in health and disease [22].
  • Interactions of HSP22 (HSPB8) with HSP20, alphaB-crystallin, and HSPB3 [11].
  • HSP22 homo-dimers are formed through N-N and N-C interactions, and HSP22-cvHSP hetero-dimers through C-C interaction [23].
  • Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates [2].
  • A single site mutant (H11-W51C) had cytoprotective activity related to MEK/ERK activation, and it blocked H11-induced apoptosis in co-transfected and Aza-C-treated cells, indicating that it is a dominant negative mutant [5].

Analytical, diagnostic and therapeutic context of HSPB8

  • Direct interaction of HspB8 with Abeta(1-42), Abeta(1-40) and Abeta(1-40) with the Dutch mutation was demonstrated by surface plasmon resonance [2].
  • This is evidenced by a significant (p < 0.001) increase in the percentage of cells positive for terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and for activation of caspase-3 and p38MAPK and by the co-localization of TUNEL+ nuclei with increased H11 levels [5].
  • By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy [16].
  • Here we have purified native HSP22 and resolved the protein into three peaks using reverse phase high performance liquid chromatography [24].
  • We demonstrate here that Merkel cells can be identified by immunohistochemistry, using a monoclonal antibody (LK2H11, Lloyd and Wilson, 1983) to neuroendocrine granules, and a monoclonal antibody (35 beta H11, Gown and Vogel, 1982) to a 54-kD keratin generally located in simple epithelia but not in stratified epithelia [25].


  1. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. Roelofs, M.F., Boelens, W.C., Joosten, L.A., Abdollahi-Roodsaz, S., Geurts, J., Wunderink, L.U., Schreurs, B.W., van den Berg, W.B., Radstake, T.R. J. Immunol. (2006) [Pubmed]
  2. 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. Wilhelmus, M.M., Boelens, W.C., Otte-Höller, I., Kamps, B., Kusters, B., Maat-Schieman, M.L., de Waal, R.M., Verbeek, M.M. Acta Neuropathol. (2006) [Pubmed]
  3. Effects of estrogen on global gene expression: identification of novel targets of estrogen action. Charpentier, A.H., Bednarek, A.K., Daniel, R.L., Hawkins, K.A., Laflin, K.J., Gaddis, S., MacLeod, M.C., Aldaz, C.M. Cancer Res. (2000) [Pubmed]
  4. A novel human gene similar to the protein kinase (PK) coding domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) codes for a serine-threonine PK and is expressed in melanoma cells. Smith, C.C., Yu, Y.X., Kulka, M., Aurelian, L. J. Biol. Chem. (2000) [Pubmed]
  5. Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. Gober, M.D., Smith, C.C., Ueda, K., Toretsky, J.A., Aurelian, L. J. Biol. Chem. (2003) [Pubmed]
  6. Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1. Li, B., Smith, C.C., Laing, J.M., Gober, M.D., Liu, L., Aurelian, L. Oncogene (2007) [Pubmed]
  7. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., Tournev, I., Hilton-Jones, D., Talbot, K., Kremensky, I., Van Den Bosch, L., Robberecht, W., Van Vandekerckhove, J., Broeckhoven, C., Gettemans, J., De Jonghe, P., Timmerman, V. Nat. Genet. (2004) [Pubmed]
  8. Human--rat muscle somatic cell hybrids form myotubes and express human muscle gene products. Quinn, C.A., Goodfellow, P.N., Povey, S., Walsh, F.S. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  9. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Carra, S., Sivilotti, M., Chávez Zobel, A.T., Lambert, H., Landry, J. Hum. Mol. Genet. (2005) [Pubmed]
  10. Immunohistochemical staining for vimentin and keratin in malignant mesothelioma. Churg, A. Am. J. Surg. Pathol. (1985) [Pubmed]
  11. Interactions of HSP22 (HSPB8) with HSP20, alphaB-crystallin, and HSPB3. Fontaine, J.M., Sun, X., Benndorf, R., Welsh, M.J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  12. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Tang, B.S., Zhao, G.H., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R.X., Zhang, F.F., Liu, X.M., Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z.G., Dai, H.P. Hum. Genet. (2005) [Pubmed]
  13. Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9. Kappé, G., Verschuure, P., Philipsen, R.L., Staalduinen, A.A., Van de Boogaart, P., Boelens, W.C., De Jong, W.W. Biochim. Biophys. Acta (2001) [Pubmed]
  14. A novel gene expressed in human keratinocytes with long-term in vitro growth potential is required for cell growth. Aurelian, L., Smith, C.C., Winchurch, R., Kulka, M., Gyotoku, T., Zaccaro, L., Chrest, F.J., Burnett, J.W. J. Invest. Dermatol. (2001) [Pubmed]
  15. Expression analysis and chromosome location of a novel gene (H11) associated with the growth of human melanoma cells. Yu, Y.X., Heller, A., Liehr, T., Smith, C.C., Aurelian, L. Int. J. Oncol. (2001) [Pubmed]
  16. H11 kinase is a novel mediator of myocardial hypertrophy in vivo. Depre, C., Hase, M., Gaussin, V., Zajac, A., Wang, L., Hittinger, L., Ghaleh, B., Yu, X., Kudej, R.K., Wagner, T., Sadoshima, J., Vatner, S.F. Circ. Res. (2002) [Pubmed]
  17. Structural instability caused by a mutation at a conserved arginine in the alpha-crystallin domain of Chinese hamster heat shock protein 27. Chávez Zobel, A.T., Lambert, H., Thériault, J.R., Landry, J. Cell Stress Chaperones (2005) [Pubmed]
  18. Some properties of human small heat shock protein Hsp22 (H11 or HspB8). Kim, M.V., Seit-Nebi, A.S., Marston, S.B., Gusev, N.B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  19. Haemonchus contortus glycoproteins contain N-linked oligosaccharides with novel highly fucosylated core structures. Haslam, S.M., Coles, G.C., Munn, E.A., Smith, T.S., Smith, H.F., Morris, H.R., Dell, A. J. Biol. Chem. (1996) [Pubmed]
  20. Crucial role of the H11-H12 loop in stabilizing the active conformation of the human mineralocorticoid receptor. Hellal-Levy, C., Fagart, J., Souque, A., Wurtz, J.M., Moras, D., Rafestin-Oblin, M.E. Mol. Endocrinol. (2000) [Pubmed]
  21. Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. Safe, S., Krishnan, V. Arch. Toxicol. Suppl. (1995) [Pubmed]
  22. Small heat shock proteins in inherited peripheral neuropathies. Dierick, I., Irobi, J., De Jonghe, P., Timmerman, V. Ann. Med. (2005) [Pubmed]
  23. Interaction of human HSP22 (HSPB8) with other small heat shock proteins. Sun, X., Fontaine, J.M., Rest, J.S., Shelden, E.A., Welsh, M.J., Benndorf, R. J. Biol. Chem. (2004) [Pubmed]
  24. In vivo modifications of the maize mitochondrial small heat stress protein, HSP22. Lund, A.A., Rhoads, D.M., Lund, A.L., Cerny, R.L., Elthon, T.E. J. Biol. Chem. (2001) [Pubmed]
  25. Identification of Merkel cells in oral epithelium using antikeratin and antineuroendocrine monoclonal antibodies. Ness, K.H., Morton, T.H., Dale, B.A. J. Dent. Res. (1987) [Pubmed]
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