Hsp27

HSPB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases HSPB1, CMT2F, HEL-S-102, HMN2B, HS.76067, HSP27, HSP28, Hsp25, SRP27, heat shock protein family B (small) member 1
External IDs OMIM: 602195 MGI: 96240 HomoloGene: 1180 GeneCards: HSPB1
Orthologs
Species Human Mouse
Entrez

3315

15507

Ensembl

ENSG00000106211

ENSMUSG00000004951

UniProt

P04792

P14602

RefSeq (mRNA)

NM_001540

NM_013560

RefSeq (protein)

NP_001531.1

NP_038588.2

Location (UCSC) Chr 7: 76.3 – 76.3 Mb Chr 5: 135.89 – 135.89 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.[3][4]

Hsp27 is a chaperone of the sHsp (small heat shock protein) group among ubiquitin, α-crystallin, Hsp20 and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation. They also take part in signal transduction.

Structure

sHsps have some structural features in common: Very characteristic is a homologous and highly conserved amino acid sequence, the so-called α-crystallin-domain at the C-terminus. These sequences consist of 80 to 100 residues with a homology between 20% and 60% and form β-sheets, which are important for the formation of stable dimers.[5][6]

The N-terminus consists of a less conserved region, the so-called WD/EPF domain, followed by a short variable sequence with a rather conservative site near the C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.[7]

This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. It is highly flexible and polar because of its negative charges.[8] Probably it functions as a mediator of solubility for hydrophobic sHsps and it stabilizes the protein and protein/substrate complexes. This was shown by elimination of the C-terminal tail in Hsp27Δ182-205[9] and in Hsp25Δ18.[10]

Oligomerization

The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers,[11][12] which exclusively have chaperone activity in vitro. Hsp27-oligomers probably consist of stable dimers, which are formed by two α-crystallin-domains of neighbouring monomers,[7] which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii[5] and wheat Hsp16.9.[6] The stable dimers aggregate to tetramers and finally form unstable oligomers.

The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits.[12][13][14] The oligomerization depends on the physiology of the cells, the phosphorylation status of Hsp27 and the exposure to stress. Stress induces an increase of expression (after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38 MAP kinase cascade by differentiating agents, mitogens, inflammatory cytokines such as TNFα and IL-1β, hydrogen peroxide and other oxidants,[15] leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps.[14] The phosphorylation plays an important role for the formation of oligomers in exponentially growing cells in vitro, but the oligomerization in tumor cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status.[16] Furthermore, it was shown that HSP27 contains an Argpyrimidine modification.[17]

In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity.[7] Therefore it is clear, that a formation of large aggregates takes place under heat shock.[13]

Cellular Localization

Hsp27 appears in many cell types, especially all types of muscle cells. It is located mainly in the cytosol, but also in the perinuclear region, endoplasmatic reticulum, and nucleus. It is overexpressed during different stages of cell differentiation and development. This suggests an essential role for Hsp27 in the differentiation of tissues.

An affinity of high expression levels of different phosphorylated Hsp27 species and muscle/neurodegenerative diseases and various cancers was observed.[18] High expression levels possibly are in inverse relation with cell proliferation, metastasis, and resistance to chemotherapy.[19] High levels of Hsp27 were also found in sera of breast cancer patients;[20] therefore Hsp27 could be a potential diagnostic marker.

Function

The main function of Hsp27 is to provide thermotolerance in vivo, cytoprotection, and support of cell survival under stress conditions. More specialized functions of Hsp27 are manifold and complex. In vitro it acts as an ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70-complex.

Hsp27 is also involved in the apoptotic signalling pathway. Hsp27 interacts with the outer mitochondrial membranes and interferes with the activation of cytochrome c/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9.[18] The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.[21] Moreover, Hsp27 phosphorylation leads to the activation of TAK1 and TAK1-p38/ERK pro-survival signaling, thus opposing TNF-α-induced apoptosis.[22]

A well documented function of Hsp27 is the interaction with actin and intermediate filaments. It prevents the formation of non-covalent filament/filament interactions of the intermediate filaments and protects actin filaments from fragmentation. It also preserves the focal contacts fixed at the cell membrane.[18]

Another function of Hsp27 is the activation of the proteasome. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitinated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB pathway, that controls a lot of processes, such as cell growth and inflammatory and stress responses.[23] The cytoprotective properties of Hsp27 result from its ability to modulate reactive oxygen species and to raise glutathione levels.

Probably Hsp27 – among other chaperones – is involved in the process of cell differentiation.[24] Changes of Hsp27 levels were observed in Ehrlich ascite cells, embryonic stem cells, normal B-cells, B-lymphoma cells, osteoblasts, keratinocytes, neurons etc. The upregulation of Hsp27 correlates with the rate of phosphorylation and with an increase of large oligomers. It is possible that Hsp27 plays a crucial role in the termination of growth.

Clinical significance

Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporin, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colonic tumors, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[25] Notably, phosphorylated Hsp27 increases human prostate cancer (PCa) cell invasion, enhances cell proliferation, and suppresses Fas-induced apoptosis in human PCa cells. Unphosphorylated Hsp27 has been shown to act as an actin capping protein, preventing actin reorganization and, consequently, cell adhesion and motility. OGX-427, which targets HSP27 through an antisense mechanism, is currently undergoing testing in clinical trials.[26]

Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[27][25] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[25] Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's corea, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[27] Protein kinase C-mediated HSPB1 phosphorylation protects against ferroptosis, an iron-dependent form of non-apoptotic cell death, by reducing iron-mediated production of lipid reactive oxygen species. These novel data support the development of Hsp-targeting strategies and, specifically, anti-HSP27 agents for the treatment of ferroptosis-mediated cancer.[28]

Interactions

Hsp27 has been shown to interact with:

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ Carper SW, Rocheleau TA, Storm FK (Nov 1990). "cDNA sequence of a human heat shock protein HSP27". Nucleic Acids Research. 18 (21): 6457. doi:10.1093/nar/18.21.6457. PMC 332574Freely accessible. PMID 2243808.
  4. ↑ Hunt CR, Goswami PC, Kozak CA (Oct 1997). "Assignment of the mouse Hsp25 and Hsp105 genes to the distal region of chromosome 5 by linkage analysis". Genomics. 45 (2): 462–3. doi:10.1006/geno.1997.4973. PMID 9344682.
  5. 1 2 Kim KK, Kim R, Kim SH (Aug 1998). "Crystal structure of a small heat-shock protein". Nature. 394 (6693): 595–9. doi:10.1038/29106. PMID 9707123.
  6. 1 2 Van Montfort R, Slingsby C, Vierling E (2001). "Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones". Advances in Protein Chemistry. Advances in Protein Chemistry. 59: 105–56. doi:10.1016/S0065-3233(01)59004-X. ISBN 9780120342594. PMID 11868270.
  7. 1 2 3 Gusev NB, Bogatcheva NV, Marston SB (May 2002). "Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins". Biochemistry. Biokhimii͡A. 67 (5): 511–9. doi:10.1023/A:1015549725819. PMID 12059769.
  8. ↑ Liao JH, Lee JS, Chiou SH (Sep 2002). "C-terminal lysine truncation increases thermostability and enhances chaperone-like function of porcine alphaB-crystallin". Biochemical and Biophysical Research Communications. 297 (2): 309–16. doi:10.1016/S0006-291X(02)02185-X. PMID 12237119.
  9. ↑ Lelj-Garolla B, Mauk AG (Jan 2005). "Self-association of a small heat shock protein". Journal of Molecular Biology. 345 (3): 631–42. doi:10.1016/j.jmb.2004.10.056. PMID 15581903.
  10. ↑ Lindner RA, Carver JA, Ehrnsperger M, Buchner J, Esposito G, Behlke J, Lutsch G, Kotlyarov A, Gaestel M (Apr 2000). "Mouse Hsp25, a small shock protein. The role of its C-terminal extension in oligomerization and chaperone action". European Journal of Biochemistry / FEBS. 267 (7): 1923–32. doi:10.1046/j.1432-1327.2000.01188.x. PMID 10727931.
  11. ↑ Haslbeck M (Oct 2002). "sHsps and their role in the chaperone network". Cellular and Molecular Life Sciences. 59 (10): 1649–57. doi:10.1007/PL00012492. PMID 12475175.
  12. 1 2 Thériault JR, Lambert H, Chávez-Zobel AT, Charest G, Lavigne P, Landry J (May 2004). "Essential role of the NH2-terminal WD/EPF motif in the phosphorylation-activated protective function of mammalian Hsp27". The Journal of Biological Chemistry. 279 (22): 23463–71. doi:10.1074/jbc.M402325200. PMID 15033973.
  13. 1 2 Ehrnsperger M, Lilie H, Gaestel M, Buchner J (May 1999). "The dynamics of Hsp25 quaternary structure. Structure and function of different oligomeric species". The Journal of Biological Chemistry. 274 (21): 14867–74. doi:10.1074/jbc.274.21.14867. PMID 10329686.
  14. 1 2 Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M (Jul 1999). "Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation". The Journal of Biological Chemistry. 274 (27): 18947–56. doi:10.1074/jbc.274.27.18947. PMID 10383393.
  15. ↑ Garrido C (May 2002). "Size matters: of the small HSP27 and its large oligomers". Cell Death and Differentiation. 9 (5): 483–5. doi:10.1038/sj/cdd/4401005. PMID 11973606.
  16. ↑ Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E, Garrido C (Oct 2000). "Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo". Oncogene. 19 (42): 4855–63. doi:10.1038/sj.onc.1203850. PMID 11039903.
  17. ↑ Gawlowski, T; Stratmann, B; Stork, I; Engelbrecht, B; Brodehl, A; Niehaus, K; Körfer, R; Tschoepe, D; Milting, H (Aug 2009). "Heat shock protein 27 modification is increased in the human diabetic failing heart". Horm Metab Res. 41 (8): 594–9. doi:10.1055/s-0029-1216374. PMID 19384818.
  18. 1 2 3 Sarto C, Binz PA, Mocarelli P (Apr 2000). "Heat shock proteins in human cancer". Electrophoresis. 21 (6): 1218–26. doi:10.1002/(SICI)1522-2683(20000401)21:6<1218::AID-ELPS1218>3.0.CO;2-H. PMID 10786894.
  19. ↑ Vargas-Roig LM, Fanelli MA, López LA, Gago FE, Tello O, Aznar JC, Ciocca DR (1997). "Heat shock proteins and cell proliferation in human breast cancer biopsy samples". Cancer Detection and Prevention. 21 (5): 441–51. PMID 9307847.
  20. ↑ Rui Z, Jian-Guo J, Yuan-Peng T, Hai P, Bing-Gen R (Apr 2003). "Use of serological proteomic methods to find biomarkers associated with breast cancer". Proteomics. 3 (4): 433–9. doi:10.1002/pmic.200390058. PMID 12687611.
  21. ↑ Charette SJ, Lavoie JN, Lambert H, Landry J (Oct 2000). "Inhibition of Daxx-mediated apoptosis by heat shock protein 27". Molecular and Cellular Biology. 20 (20): 7602–12. doi:10.1128/MCB.20.20.7602-7612.2000. PMC 86317Freely accessible. PMID 11003656.
  22. 1 2 3 4 Qi Z, Shen L, Zhou H, Jiang Y, Lan L, Luo L, Yin Z (Jul 2014). "Phosphorylation of heat shock protein 27 antagonizes TNF-α induced HeLa cell apoptosis via regulating TAK1 ubiquitination and activation of p38 and ERK signaling". Cellular Signalling. 26 (7): 1616–25. doi:10.1016/j.cellsig.2014.03.015. PMID 24686082.
  23. ↑ Parcellier A, Schmitt E, Gurbuxani S, Seigneurin-Berny D, Pance A, Chantôme A, Plenchette S, Khochbin S, Solary E, Garrido C (Aug 2003). "HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation". Molecular and Cellular Biology. 23 (16): 5790–802. doi:10.1128/MCB.23.16.5790-5802.2003. PMC 166315Freely accessible. PMID 12897149.
  24. ↑ Arrigo AP (Feb 2005). "In search of the molecular mechanism by which small stress proteins counteract apoptosis during cellular differentiation". Journal of Cellular Biochemistry. 94 (2): 241–6. doi:10.1002/jcb.20349. PMID 15546148.
  25. 1 2 3 Wang X, Wang Q, Lin H, Li S, Sun L, Yang Y (Feb 2013). "HSP72 and gp96 in gastroenterological cancers". Clinica Chimica Acta; International Journal of Clinical Chemistry. 417: 73–9. doi:10.1016/j.cca.2012.12.017. PMID 23266770.
  26. ↑ Voll EA, Ogden IM, Pavese JM, Huang X, Xu L, Jovanovic BD, Bergan RC (May 2014). "Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression". Oncotarget. 5 (9): 2648–63. doi:10.18632/oncotarget.1917. PMID 24798191.
  27. 1 2 Heywood A, Oppenheimer S, Heywood P, Jolley D (Sep 1989). "Behavioral effects of iron supplementation in infants in Madang, Papua New Guinea". The American Journal of Clinical Nutrition. 50 (3 Suppl): 670–84. doi:10.1007/s00018-004-4464-6. PMC 2773841Freely accessible. PMID 15770419.
  28. ↑ Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, Wang H, Cao L, Tang D (Mar 2015). "HSPB1 as a novel regulator of ferroptotic cancer cell death". Oncogene. 34: 5617–25. doi:10.1038/onc.2015.32. PMID 25728673.
  29. 1 2 3 Fu L, Liang JJ (Feb 2002). "Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay". The Journal of Biological Chemistry. 277 (6): 4255–60. doi:10.1074/jbc.M110027200. PMID 11700327.
  30. ↑ Kato K, Shinohara H, Goto S, Inaguma Y, Morishita R, Asano T (Apr 1992). "Copurification of small heat shock protein with alpha B crystallin from human skeletal muscle". The Journal of Biological Chemistry. 267 (11): 7718–25. PMID 1560006.
  31. ↑ Sinsimer KS, Gratacós FM, Knapinska AM, Lu J, Krause CD, Wierzbowski AV, Maher LR, Scrudato S, Rivera YM, Gupta S, Turrin DK, De La Cruz MP, Pestka S, Brewer G (Sep 2008). "Chaperone Hsp27, a novel subunit of AUF1 protein complexes, functions in AU-rich element-mediated mRNA decay". Molecular and Cellular Biology. 28 (17): 5223–37. doi:10.1128/MCB.00431-08. PMC 2519747Freely accessible. PMID 18573886.
  32. ↑ Sun X, Fontaine JM, Rest JS, Shelden EA, Welsh MJ, Benndorf R (Jan 2004). "Interaction of human HSP22 (HSPB8) with other small heat shock proteins". The Journal of Biological Chemistry. 279 (4): 2394–402. doi:10.1074/jbc.M311324200. PMID 14594798.
  33. ↑ 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, Van Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V (Jun 2004). "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy". Nature Genetics. 36 (6): 597–601. doi:10.1038/ng1328. PMID 15122253.
  34. ↑ Jia Y, Ransom RF, Shibanuma M, Liu C, Welsh MJ, Smoyer WE (Oct 2001). "Identification and characterization of hic-5/ARA55 as an hsp27 binding protein". The Journal of Biological Chemistry. 276 (43): 39911–8. doi:10.1074/jbc.M103510200. PMID 11546764.

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