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HSP47 and Its Involvement in Fibrotic Disorders

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Chaperokine Activity of Heat Shock Proteins

Part of the book series: Heat Shock Proteins ((HESP,volume 16))

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Abstract

Heat shock protein 47 (HSP47) is a collagen specific chaperone that is critical for the synthesis and maturation of collagen. It is encoded by the gene of SERPINH1 and belongs to the serpin superfamily, while it lacks the active site essential for proteinase inhibition. HSP47 is an endoplasmic reticulum (ER) resident protein having the RDEL retention signal at C terminus. As a collagen chaperone, HSP47 preferentially recognizes the Gly-X-Y on procollagen triple helix. It binds to procollagen transiently once the nascent procollagen enters the ER to prevent the misfolding and aggregation of the procollagen, afterwards it dissociates from the triple helix at the cis-Golgi and cycles back to ER under the lead of RDEL signal. HSP47 expresses strictly in parallel with collagen proteins by collagen-producing cells, and it has been demonstrated to be involved in various fibrotic disorders including liver, lung and skin fibrosis. The specialty and necessity of HSP47 for collagen synthesis make it a good candidate for the treatment of fibrotic diseases. Several approaches designed targeting HSP47 has shown promising therapeutic effect as investigated in experimental animal models. This chapter briefly reviews the recent advances of HSP47 as collagen chaperone and its participant in fibrotic disorders.

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Abbreviations

BiP:

Immunoglobulin heavy chain-binding protein

CCI4:

Carbon tetrachloride

CTGF:

Connective tissue growth factor

ECM:

Extracellular matrix

ER:

Endoplasmic reticulum

ERQC:

ER quality control

Grp94:

94-kDa glucose-regulated protein

HSCs:

Hepatic stellate cells

HSE:

Heat shock element

HSF1:

Heat shock transcription factor I

HSP:

Heat shock proteins

IL:

Interleukin

IPF:

Idiopathic pulmonary fibrosis

KLF:

Kruppel-like factor

NASH:

Nonalcoholic steatohepatitis

P4H:

Prolyl 4-hydroxylase

PBMC:

Peripheral blood mononuclear cell

PDI:

Protein disulphide isomerase

SLE:

Systemic lupus erythematosus

SSc:

Systemic sclerosis

TGF-β:

Transform growth factor β

References

  • Araki K, Nagata K (2011) Protein folding and quality control in the ER. Cold Spring Harb Perspect Biol 3:a007526

    Article  Google Scholar 

  • Asea A (2003) Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 9:25–33

    PubMed  PubMed Central  Google Scholar 

  • Asea A (2005) Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 11:34–45

    PubMed  PubMed Central  Google Scholar 

  • Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    Article  CAS  Google Scholar 

  • Becker J, Craig EA (1994) Heat-shock proteins as molecular chaperones. Eur J Biochem 219:11–23

    Article  CAS  Google Scholar 

  • Brown KE, Broadhurst KA, Mathahs MM, Brunt EM, Schmidt WN (2005) Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver. Lab Inv; J Tech Methods Pathol 85:789–797

    Article  CAS  Google Scholar 

  • Cates GA, Nandan D, Brickenden AM, Sanwal BD (1987) Differentiation defective mutants of skeletal myoblasts altered in a gelatin-binding glycoprotein. Biochem Cell Biol Biochim Biol Cell 65:767–775

    Article  CAS  Google Scholar 

  • Chi HH, Hua KF, Lin YC et al (2017) IL-36 signaling facilitates activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in renal inflammation and fibrosis. J Am Soc Nephrol 28:2022–2037

    Article  CAS  Google Scholar 

  • Chu H, Wu T, Wu W et al (2015) Involvement of collagen-binding heat shock protein 47 in scleroderma-associated fibrosis. Protein Cell 6:589–598

    Article  CAS  Google Scholar 

  • Chu H, Shi Y, Jiang S et al (2017) Treatment effects of the traditional Chinese medicine Shenks in bleomycin-induced lung fibrosis through regulation of TGF-beta/Smad3 signaling and oxidative stress. Sci Rep 7:2252

    Article  Google Scholar 

  • Di Paola R, Talero E, Galuppo M et al (2011) Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis. Respir Res 12:41

    Article  Google Scholar 

  • Fujimoto M, Hamaguchi Y, Yazawa N, Komura K, Takehara K, Sato S (2004) Autoantibodies to a collagen-specific molecular chaperone, heat-shock protein 47, in systemic sclerosis. Clin Exp Immunol 138:534–539

    Article  CAS  Google Scholar 

  • Furst DE, Fernandes AW, Iorga SR, Greth W, Bancroft T (2012) Epidemiology of systemic sclerosis in a large US managed care population. J Rheumatol 39:784–786

    Article  Google Scholar 

  • Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355:33–45

    Article  CAS  Google Scholar 

  • Gonzalez Santander R, Plasencia Arriba MA, Martinez Cuadrado G et al (1999) Intracellular biogenesis of collagen fibrils in ‘activated fibroblasts’ of tendo Achillis. An ultrastructural study in the New Zealand rabbit. J Bone Jt Surg Br 81:522–530

    Article  CAS  Google Scholar 

  • Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T (2007a) Antisense oligonucleotide inhibition of heat shock protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats. Respir Res 8:37

    Article  Google Scholar 

  • Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T (2007b) An antisense oligonucleotide to HSP47 inhibits paraquat-induced pulmonary fibrosis in rats. Toxicology 236:199–207

    Article  CAS  Google Scholar 

  • Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T, Yoshioka H (2007c) Coexpression of HSP47 gene and type I and type III collagen genes in LPS-induced pulmonary fibrosis in rats. Lung 185:31–37

    Article  CAS  Google Scholar 

  • Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, Varga J (2014) Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol 66:1967–1978

    Article  CAS  Google Scholar 

  • Hirata H, Yamamura I, Yasuda K et al (1999) Separate cis-acting DNA elements control cell type- and tissue-specific expression of collagen binding molecular chaperone HSP47. J Biol Chem 274:35703–35710

    Article  CAS  Google Scholar 

  • Hirayoshi K, Kudo H, Takechi H et al (1991) HSP47: a tissue-specific, transformation-sensitive, collagen-binding heat shock protein of chicken embryo fibroblasts. Mol Cell Biol 11:4036–4044

    Article  CAS  Google Scholar 

  • Honzawa Y, Nakase H, Shiokawa M et al (2014) Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn’s disease. Gut 63:1902–1912

    Article  CAS  Google Scholar 

  • Ishida Y, Nagata K (2011) Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol 499:167–182

    Article  CAS  Google Scholar 

  • Ishida Y, Kubota H, Yamamoto A, Kitamura A, Bachinger HP, Nagata K (2006) Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis. Mol Biol Cell 17:2346–2355

    Article  CAS  Google Scholar 

  • Ishii H, Mukae H, Kakugawa T et al (2003) Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy. Am J Physiol Lung Cell Mol Physiol 285:L957–L963

    Article  CAS  Google Scholar 

  • Ito S, Nagata K (2017) Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone. Semin Cell Dev Biol 62:142–151

    Article  CAS  Google Scholar 

  • Iwashita T, Kadota J, Naito S et al (2000) Involvement of collagen-binding heat shock protein 47 and procollagen type I synthesis in idiopathic pulmonary fibrosis: contribution of type II pneumocytes to fibrosis. Hum Pathol 31:1498–1505

    Article  CAS  Google Scholar 

  • Kakugawa T, Mukae H, Hayashi T et al (2004) Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J 24:57–65

    Article  CAS  Google Scholar 

  • Kakugawa T, Mukae H, Hishikawa Y et al (2010) Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis. Virchows Archiv: Int J Pathol 456:309–315

    Article  CAS  Google Scholar 

  • Kakugawa T, Yokota S, Ishimatsu Y et al (2013) Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones 18:581–590

    Article  CAS  Google Scholar 

  • Kawasaki K, Ushioda R, Ito S, Ikeda K, Masago Y, Nagata K (2015) Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J Biol Chem 290:3639–3646

    Article  CAS  Google Scholar 

  • Kiang JG, Tsokos GC (1998) Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther 80:183–201

    Article  CAS  Google Scholar 

  • Koide T, Asada S, Nagata K (1999) Substrate recognition of collagen-specific molecular chaperone HSP47. Structural requirements and binding regulation. J Biol Chem 274:34523–34526

    Article  CAS  Google Scholar 

  • Koide T, Aso A, Yorihuzi T, Nagata K (2000) Conformational requirements of collagenous peptides for recognition by the chaperone protein HSP47. J Biol Chem 275:27957–27963

    CAS  PubMed  Google Scholar 

  • Koide T, Takahara Y, Asada S, Nagata K (2002) Xaa-Arg-Gly triplets in the collagen triple helix are dominant binding sites for the molecular chaperone HSP47. J Biol Chem 277:6178–6182

    Article  CAS  Google Scholar 

  • Koide T, Nishikawa Y, Asada S et al (2006) Specific recognition of the collagen triple helix by chaperone HSP47. II. The HSP47-binding structural motif in collagens and related proteins. J Biol Chem 281:11177–11185

    Article  CAS  Google Scholar 

  • Kolahian S, Fernandez IE, Eickelberg O, Hartl D (2016) Immune mechanisms in pulmonary fibrosis. Am J Respir Cell Mol Biol 55:309–322

    Article  CAS  Google Scholar 

  • Kurkinen M, Taylor A, Garrels JI, Hogan BL (1984) Cell surface-associated proteins which bind native type IV collagen or gelatin. J Biol Chem 259:5915–5922

    CAS  PubMed  Google Scholar 

  • Kuroda K, Tsukifuji R, Shinkai H (1998) Increased expression of heat-shock protein 47 is associated with overproduction of type I procollagen in systemic sclerosis skin fibroblasts. J Invest Dermatol 111:1023–1028

    Article  CAS  Google Scholar 

  • Lamande SR, Bateman JF (1999) Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and molecular chaperones. Semin Cell Dev Biol 10:455–464

    Article  CAS  Google Scholar 

  • Marra F (1999) Hepatic stellate cells and the regulation of liver inflammation. J Hepatol 31:1120–1130

    Article  CAS  Google Scholar 

  • Marutani T, Yamamoto A, Nagai N, Kubota H, Nagata K (2004) Accumulation of type IV collagen in dilated ER leads to apoptosis in Hsp47-knockout mouse embryos via induction of CHOP. J Cell Sci 117:5913–5922

    Article  CAS  Google Scholar 

  • Masago Y, Hosoya A, Kawasaki K et al (2012) The molecular chaperone Hsp47 is essential for cartilage and endochondral bone formation. J Cell Sci 125:1118–1128

    Article  CAS  Google Scholar 

  • Masuda H, Fukumoto M, Hirayoshi K, Nagata K (1994) Coexpression of the collagen-binding stress protein HSP47 gene and the alpha 1(I) and alpha 1(III) collagen genes in carbon tetrachloride-induced rat liver fibrosis. J Clin Invest 94:2481–2488

    Article  CAS  Google Scholar 

  • Myllyharju J (2003) Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol: J Int Soc Matrix Biol 22:15–24

    Article  CAS  Google Scholar 

  • Nagai N, Hosokawa M, Itohara S et al (2000) Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol 150:1499–1506

    Article  CAS  Google Scholar 

  • Nagata K (1996) Hsp47: a collagen-specific molecular chaperone. Trends Biochem Sci 21:22–26

    Article  CAS  Google Scholar 

  • Nagata K (2003) HSP47 as a collagen-specific molecular chaperone: function and expression in normal mouse development. Semin Cell Dev Biol 14:275–282

    Article  CAS  Google Scholar 

  • Nagata K, Saga S, Yamada KM (1986) A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein. J Cell Biol 103:223–229

    Article  CAS  Google Scholar 

  • Nagata K, Hirayoshi K, Obara M, Saga S, Yamada KM (1988) Biosynthesis of a novel transformation-sensitive heat-shock protein that binds to collagen. Regulation by mRNA levels and in vitro synthesis of a functional precursor. J Biol Chem 263:8344–8349

    CAS  PubMed  Google Scholar 

  • Naitoh M, Hosokawa N, Kubota H et al (2001) Upregulation of HSP47 and collagen type III in the dermal fibrotic disease, keloid. Biochem Biophys Res Commun 280:1316–1322

    Article  CAS  Google Scholar 

  • Nakai A, Satoh M, Hirayoshi K, Nagata K (1992) Involvement of the stress protein HSP47 in procollagen processing in the endoplasmic reticulum. J Cell Biol 117:903–914

    Article  CAS  Google Scholar 

  • Ning ZW, Luo XY, Wang GZ et al (2017) MicroRNA-21 mediates angiotensin II-induced liver fibrosis by activating NLRP3 Inflammasome/IL-1beta Axis via targeting Smad7 and Spry1. Antioxid Redox Signal 27:1–20

    Article  CAS  Google Scholar 

  • Nishino T, Miyazaki M, Abe K et al (2003) Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress peritoneal fibrosis in rats. Kidney Int 64:887–896

    Article  CAS  Google Scholar 

  • Noble PW, Barkauskas CE, Jiang D (2012) Pulmonary fibrosis: patterns and perpetrators. J Clin Invest 122:2756–2762

    Article  CAS  Google Scholar 

  • Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE (2015) Pathogenesis of systemic sclerosis. Front Immunol 6:272

    Article  Google Scholar 

  • Ryu C, Sun H, Gulati M et al (2017) Extracellular mitochondrial DNA is generated by fibroblasts and predicts death in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 196:1571–1581

    Article  CAS  Google Scholar 

  • Saga S, Nagata K, Chen WT, Yamada KM (1987) pH-dependent function, purification, and intracellular location of a major collagen-binding glycoprotein. J Cell Biol 105:517–527

    Article  CAS  Google Scholar 

  • Sasaki H, Sato T, Yamauchi N et al (2002) Induction of heat shock protein 47 synthesis by TGF-beta and IL-1 beta via enhancement of the heat shock element binding activity of heat shock transcription factor 1. J Immunol 168:5178–5183

    Article  CAS  Google Scholar 

  • Sato Y, Murase K, Kato J et al (2008) Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 26:431–442

    Article  CAS  Google Scholar 

  • Satoh M, Hirayoshi K, Yokota S, Hosokawa N, Nagata K (1996) Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen. J Cell Biol 133:469–483

    Article  CAS  Google Scholar 

  • Taguchi T, Razzaque MS (2007) The collagen-specific molecular chaperone HSP47: is there a role in fibrosis? Trends Mol Med 13:45–53

    Article  CAS  Google Scholar 

  • Takechi H, Hirayoshi K, Nakai A, Kudo H, Saga S, Nagata K (1992) Molecular cloning of a mouse 47-kDa heat-shock protein (HSP47), a collagen-binding stress protein, and its expression during the differentiation of F9 teratocarcinoma cells. Eur J Biochem 206:323–329

    Article  CAS  Google Scholar 

  • Tasab M, Batten MR, Bulleid NJ (2000) Hsp47: a molecular chaperone that interacts with and stabilizes correctly-folded procollagen. EMBO J 19:2204–2211

    Article  CAS  Google Scholar 

  • Tasab M, Jenkinson L, Bulleid NJ (2002) Sequence-specific recognition of collagen triple helices by the collagen-specific molecular chaperone HSP47. J Biol Chem 277:35007–35012

    Article  CAS  Google Scholar 

  • Toonkel RL, Hare JM, Matthay MA, Glassberg MK (2013) Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med 188:133–140

    Article  Google Scholar 

  • Ueno M, Maeno T, Nomura M et al (2011) Hypoxia-inducible factor-1alpha mediates TGF-beta-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 300:L740–L752

    Article  CAS  Google Scholar 

  • Vaillant P, Menard O, Vignaud JM, Martinet N, Martinet Y (1996) The role of cytokines in human lung fibrosis. Monaldi Arch Chest Dis Arch Monaldi mal torace/Fondazione clin lav, IRCCS [and] Ist clin tisiologica mal apparato respiratorio, Univ Napoli, Secondo ateneo 51:145–152

    CAS  Google Scholar 

  • Veraldi KL, Hsu E, Feghali-Bostwick CA (2010) Pathogenesis of pulmonary fibrosis in systemic sclerosis: lessons from interstitial lung disease. Curr Rheumatol Rep 12:19–25

    Article  Google Scholar 

  • Wang Z, Li L (2008) Adenovirus-mediated RNA interference against collagen-specific molecular chaperone 47-KDa heat shock protein suppresses scar formation on mouse wounds. Cell Biol Int 32:484–493

    Article  CAS  Google Scholar 

  • Wang ZL, Inokuchi T, Ikeda H et al (2002) Collagen-binding heat shock protein HSP47 expression during healing of fetal skin wounds. Int J Oral Maxillofac Surg 31:179–184

    Article  CAS  Google Scholar 

  • Wang Z, Inokuchi T, Nemoto TK, Uehara M, Baba TT (2003) Antisense oligonucleotide against collagen-specific molecular chaperone 47-kDa heat shock protein suppresses scar formation in rat wounds. Plast Reconstr Surg 111:1980–1987

    Article  Google Scholar 

  • Widmer C, Gebauer JM, Brunstein E et al (2012) Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition. Proc Natl Acad Sci U S A 109:13243–13247

    Article  CAS  Google Scholar 

  • Wolters PJ, Collard HR, Jones KD (2014) Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9:157–179

    Article  CAS  Google Scholar 

  • Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4:583–594

    Article  CAS  Google Scholar 

  • Wynn TA (2011) Integrating mechanisms of pulmonary fibrosis. J Exp Med 208:1339–1350

    Article  CAS  Google Scholar 

  • Young A, Koduri G, Batley M et al (2007) Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology 46:350–357

    Article  CAS  Google Scholar 

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Acknowledgements

This study was partially supported by the grants from the National Science Foundation of China (81470254, 31521003, 81770066), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the International S & T Cooperation Program of China (2013DFA30870).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China

    Haiyan Chu, Li Jin & Jiucun Wang

  2. Human Phenome Institute, Fudan University, Shanghai, China

    Li Jin & Jiucun Wang

  3. Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China

    Jiucun Wang

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  1. Haiyan Chu
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  2. Li Jin
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  3. Jiucun Wang
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Correspondence to Jiucun Wang .

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Editors and Affiliations

  1. Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Chu, H., Jin, L., Wang, J. (2019). HSP47 and Its Involvement in Fibrotic Disorders. In: Asea, A., Kaur, P. (eds) Chaperokine Activity of Heat Shock Proteins . Heat Shock Proteins, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-030-02254-9_14

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