Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 575
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
HSPD1 (Heat Shock 60kDa Protein 1) Cappello Francesco, Conway de Macario Everly, Macario Alberto JL
Department of Experimental Biomedicine, Clinical Neuroscience, Section of Human Anatomy,
University of Palermo, Palermo, Italy;, Euro-Mediterranean Institute of Science, Technology,
Palermo, Italy (FC); Department of Microbiology, Immunology, School of Medicine, University of
Maryland at Baltimore; Institute of Marine, Environmental Technology (IMET); Columbus Center,
Baltimore, MD 21202, USA (ECdeM); Department of Microbiology, Immunology, School of
Medicine, University of Maryland at Baltimore,, Institute of Marine, Environmental Technology
(IMET), Columbus Center, Baltimore, MD 21202, USA;, Euro-Mediterranean Institute of Science,
Technology, Palermo, Italy (AJLM)
Published in Atlas Database: October 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/HSPD1ID40888ch2q33.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62324/10-2014-HSPD1ID40888ch2q33.pdf DOI: 10.4267/2042/62324
This article is an update of : HSPD1 (Heat Shock 60kDa Protein 1). Atlas Genet Cytogenet Oncol Haematol 2015;19(9) Faried A, Faried LS. HSPD1 (Heat Shock 60kDa Protein 1). Atlas Genet Cytogenet Oncol Haematol 2007;11(3)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract The HSPD1 gene encodes a protein known as HSP60
or Hsp60, also commonly referred to as Cpn60. This
protein is a molecular chaperone typically localized
inside mitochondria where it forms a chaperoning
machine with HSP10 (encoded by the HSPE1 gene),
also called Cpn10, to assist protein folding inside the
organelle. Hsp60 also occurs in the cytosol, plasma-
cell membrane, intercellular space, and blood. Its
functions in all these extramitochondrial locations
are poorly understood. While the canonical functions
of Hsp60 are considered to be cytoprotective, anti-
stress and maintenance of protein homeostasis, other
roles are currently being investigated. For example,
Hsp60 participates in the pathogenesis of diseases in
various ways in certain types of cancer, and chronic
inflammatory and autoimmune pathological
conditions. These are considered chaperonopathies
by mistake, in which a normal chaperone (normal at
least as far as it can be determined by current
methods to study the structure of a molecule
available only at extremely low concentrations and
quantities) turns against the organism instead of
protecting it, favouring the growth and
dissemination of cancer cells, or the initiation-
progression of inflammation, for instance. In
addition, Hsp60 mutations cause at least two types of
severe genetic chaperonopathies. All this knowledge
is expanding nowadays clearly pointing to Hsp60 as
a potential target for chaperonotherapy by
replacement when it is defective or by inhibition
when it is pathogenic.
Keywords
HSPD1, HSP60, Cpn60, GroEL, chaperonin,
chaperone, protein folding, mitochondria,
extramitochondrial sites, cancer, chronic
inflammatory conditions, autoimmune diseases,
chaperonopathies by mistake, chaperonotherapy
Identity
Other names: HSP60, HSP65, HuCHA60,
Chaperonin 60kDa (CPN60), GROEL, SPG13
HGNC (Hugo): HSPD1
Location: 2q33.1
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 576
Hsp60 and Hsp10 protein/gene/genomic data.
The molecular anatomy of the human Hsp60: structural domains. Left: The anatomy of the human Hsp60: structural domains. The cartoon represents a three-dimensional model of the human Hsp60 monomer showing its three structural domains:
apical in green, intermediate in yellow and equatorial in red. Right: This picture presents the ATP and Mg+/K+ binding sites on Hsp60. Particularly it shows two highly conserved sequences: 52-DGVTVAKEI-60 (orange-brown), and 85-AGDGTTTATVL-95 (magenta) corresponding to the binding sites for Mg+/K+ (green and yellow spheres, respectively) and ATP/ADP (red). Source:
Cappello et al., Expert Opin Ther Targets. 2014 ; 18 (2) : 185-208. PMID 24286280.
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 577
DNA/RNA
Description
The human HSP60 gene (HSPD1) contains 12 exons
and 11 introns and was predicted to span over
approximately 13 kb of the genomic DNA. The first
exon is non-coding region (Hansen et al., 2003;
Mukherjee et al., 2010).
Transcription
Two transcript variants encoding the same protein
have been identified for HSPD1
http://www.ncbi.nlm.nih.gov/gene/3329; Mukherjee
et al., 2010).
Pseudogene
Twelve pseudogenes located on chromosome 3, 4, 5,
6, 8 and 12 have been associated with HSP60
(Mukherjee et al., 2010).
Protein
Description
The HSP60 consists of 573 amino acids
corresponding to a molecular weight of 61.05 kDa
(Mukherjee et al., 2010). The HSP60 protein are
abundant proteins of eubacteria genomes and
mitochondria in eukaryotes, and also occurs in other
locations, such as the cellular cytosol, plasma-cell
membrane, and extracellular space (including blood)
in eukaryotic organisms.
HSP60 belongs to the chaperone subgroup called
chaperonins, of which two varieties are known:
chaperonins of Group I and chaperonins of Group II.
The former include the human HSP60 typically
present in the mitochondria (but also occurring in
other locations as described above) and the bacterial
GroEL. Chaperonins of Group II include the
archaeal thermosome subunits and the cytosolic
chaperonin CCT (Chaperonin-containing TCP-1).
The human HSP60 and the bacterial GroEL form
oligomers: seven monomers associate to form a ring
and two rings associate end to end to build a large
chaperoning machine of fourteen subunits, all
identical. This tetradecamer is the HSP60 functional
chaperoning complex that associates with Hsp60 and
requires ATP and ATPase activity for the folding of
substrates (Cappello et al., 2014).
Expression
HSP60 expression is virtually ubiquitous, since it
can be found in cells of different tissues and organs,
including immune system, epithelial tissue and other
cells (Cappello et al., 2011a). However, sometimes
its levels can be under the threshold of
detectability by immunomorphology or
immunoblotting.
It can also be found in the blood (Shamaei-Tousi et
al., 2007).
Localisation
HSP60 subcellular localization is mainly in the
mitochondria, but it also occurs in extra-
mitochondrial sites such as the cytosol, cell surface,
peroxisomes, and the endoplasmic reticulum (Soltys
and Gupta, 1996; Soltys and Gupta, 1999; Gupta et
al., 2008).
Levels of extramitochondrial localization increase
during inflammatory states (Rodolico et al., 2010;
Tomasello et al., 2011; Cappello et al., 2011b) and
tumorigenesis (Cappello et al., 2008; Cappello et al.,
2011c; Campanella et al., 2012; Rappa et al., 2012).
Function
Assisting mitochondrial protein folding, unfolding,
and degradation (Bukau and Horwich, 1998; Fink,
1999; Slavotinek and Biesecker, 2001; Thirumalai
and Lorimer, 2001; Corrao et al., 2010).
HSP60 also have anti-apoptosis and pro-apoptosis
roles in different pathophysiologic conditions such
as heart failure (Knowlton et al., 1998; Kirchhoff et
al., 2002; Gupta and Knowlton, 2005; Lin et al,
2007; Kim et al., 2009) and cancer (Chandra et al.,
2007; Campanella et al., 2008).
Homology
Up to now more than 150 homologues of HSP60
sequences with pair-wise similarity extending from
40-100% at the amino acid level. Among these
homologues one can mention those from rat rat
(Rattus norvegicus), pufferfish (Fugu rubripes),
zebrafish (Danio rerio), the nematode
Caenorhabditis elegans, mouse (Mus musculus), and
Chlamydia trachomatis (Gupta, 1995). Moreover,
Hsp60 presents a high structural homology with
other human proteins, that may act as autoantigen,
such as acetylcholine receptor, thyroglobulin, etc.
(Jones et al., 1993).
The high homology between Hsp60 of several
bacterial species and the human protein led to
postulate its involvement in molecular mimicry
phenomena with pathogenic implications
(Campanella et al., 2009; Cappello et al., 2009).
Moreover, the high homology between human and
bacterial Hsp60 and other human autoantigens led to
postulate its role in the autoimmune manifestations
of some autoimmune diseases, such as myasthenia
gravis (Cappello et al., 2010; Marino Gammazza et
al., 2012) and Hashimoto's thyroiditis (Marino
Gammazza et al., 2014).
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 578
The human hsp60 genes and pseudogenes: genomic data. Source: Mukherjee et al. BMC Evolutionary Biology 2010 10:64. PMID 20193073
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 579
Hsp60 presence and localization in normal tissues. Top: Normal human bronchial mucosa. Ciliated cells present Hsp60 positivity by immunohistochemistry (IHC) in the cytosol (red spots, see arrow for example). Bottom: Normal human colonic
mucosa. Intestinal cells do not show any positivity for Hsp60 at IHC, since the protein is under the threshold of detectability. Modified from: Cappello et al., Methods Mol Biol. 2011 ; 787 : 245-254. PMID 21898240
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 580
Hsp60 localization localization in pathologic tissues. Top: Epithelial cell of inflamed colonic mucosa (patient with ulcerative colitis) showing Hsp60 positivity (immunogold) in cytosol (arrows). Modfied from Tomasello et al., 2011). Bottom: Pulmonary mucoepidermoid carcinoma cell (H292) showing Hsp60 positivity (immunogold) in cytosol and at plasma-cell membrane level
(arrows). Inset: a classical mitochondrial positivity for Hsp60.Modified from Campanella et al., PLoS One. 2012 ; 7 (7) : e42008. PMID 22848686
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 581
Hsp60 function. Hsp60 works in cooperation with Hsp10, its co-chaperonin, to assist protein folding of unfolded mitochondrial proteins by an ATP dependent mechanism. Modified from www.pdbj.org.
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
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Mutations
Germinal Not known in Homo sapiens.
Somatic Hereditary spastic paraplegia (SPG13) is associated
with a mutation in the HSP60 gene: the amino acid
72 Valine is changed to Isoleucine (Hansen et al.,
2002).
MitCHAP-60 disease is associated with a mutation
in the HSP60 gene: The amino acid 29 Aspartic acid
is changed to Glycine (Magen et al., 2008).
General note: HSP60 expression (mRNA) and levels (protein)
were elevated, decreased or without changes in a
number of cancers studied by independent groups
with various techniques.
For a review on this topic see: Czarnecka et al., 2006;
Cappello et al., 2008; Rappa et al., 2012; Macario et
al., 2013).
Moreover, cancer cells, but not the normal
counterparts release HSP60 via exosomes
(Merendino et al., 2010; Campanella et al., 2012).
Further studies on this topic are currently under way
to better understand why Hsp60 levels change during
carcinogenesis and what is the role of this protein in
cancer progression
Epigenetics Not known in Homo sapiens.
Implicated in
Autoimmune diseases
Note
First clinical trials using HSP60 (peptide 277) has
been tested in type-2 diabetes.
Disease
HSP60 has been implicated in T cell activation and
cause inflammatory reaction. It has been involved in
the pathogenesis of a number of autoimmune
diseases and inflammatory conditions such as type-1
diabetes, juvenile chronic arthritis, atherosclerosis,
Crohn disease, rheumatoid arthritis, systemic lupus
erythematosus, Sjogren syndrome, Hashimoto
thyroiditis, and myasthenia gravis (Campanella et
al., 2009; Cappello et al., 2009; Cappello et al., 2010;
Marino Gammazza et al., 2012; Marino Gammazza
et al., 2014).
Colon cancer
Note
For a review on Hsp60 in colon cancer, see Cappello
et al., 2011c.
Disease
Hsp60 expression and levels were increased in colon
cancer of various grades and stages compared to
controls (Cappello et al., 2005a). This has been
confirmed by other independent groups (Mori et al.,
2005; He et al., 2007).
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 583
Prognosis
Hsp60 has been described as a potential serum
marker for colorectal cancer (Hamelin et al., 2011).
Oncogenesis
Hsp60 levels increase gradually through the
carcinogenic steps (i.e., normal-to-dysplasia-to-
carcinoma sequence) and Hsp60 is a good marker to
distinguish dysplastic from normal cells (Cappello et
al., 2003a).
Lung cancer.
Note
The four major histological types of carcinoma of the
lung are: squamous cell carcinoma (SCC),
adenocarcinoma (AD), small cell carcinoma
(SCLC), and large cell carcinoma (LCC). In some
cases there can be a combination of histological
patterns (Husain and Kumar, 2005).
Disease
Hsp60 levels were decreased in adenocarcinoma and
adenosquamous carcinoma compared to controls
(Cappello et al., 2005b; Cappello et al., 2006a).
However, this has not been confirmed by another
independent group (Xu et al., 2011) that in a series
of lung adenocarcinomas found increased levels of
Hsp60 compared to controls. The authors postulated
that the possible reason to explain this contrasting
data may be two: different TNM stages and different
part of the tumor biopsied (e.g., central versus
periphery).
Prognosis
Hsp60 levels were significantly correlated with
TNM stage of the tumor and Eastern Cooperative
Oncology Group performance status (Xu et al.,
2011). Multivariate statistical analysis showed that
patient age, pathological T stage, N stage, and Hsp60
expression were independent prognostic indicators
with regard to disease-free survival (Xu et al., 2011).
Oncogenesis
Hsp60 levels decrease gradually through
carcinogenetic steps of lung (i.e., normal-to-
dysplasia-to-carcinoma sequence) (Cappello et al.,
2005b; Cappello et al., 2006a).
Prostate cancer
Note
Prostate cancer is preceded by the so called 'prostate
intraneoplastic lesion' or PIN, a dysplastic
(pretumoral) lesion.
Prostatic hyperplasia is not considered a
preneoplastic condition (Bostwick and Chen, 2012).
Gleason score is an index of malignancy: the higher
it is, the worse is the prognosis (Egevad et al., 2012).
Prostate specific antigen (PSA) is a serum marker
used for prostate cancer diagnosis and follow-up
(Loeb et al., 2014).
Disease
Many studies have shown that Hsp60 levels are
increased in prostate cancer, using
immunohistochemistry (Cornford et al., 2000;
Cappello et al., 2003b; Johansson et al., 2006), and
proteomics (Skyortsov et al., 2011). HSP60 was
significantly increased in both early and advanced
prostate cancers when compared with non-neoplastic
prostatic epithelium (Cornford et al., 2000). In non-
malignant prostate, HSP60-staining is localized in
the glandular compartment, particularly basal
epithelial cells. In prostate cancer, most epithelial
cells showed moderate to strong staining without
apparent correlation between staining intensity and
Gleason grade (Johansson et al., 2006).
Prognosis
Recurrence-free survival in patients with strong
HSP60 staining was shorter than in those with weak
levels (Glaessgen et al., 2008). In another study, the
levels of HSP60 were significantly increased in
tumors with high Gleason score. HSP60 expression
was also significantly associated with initial serum
PSA levels and with the presence of lymph node
metastasis (Castilla et al., 2010).
Oncogenesis
HSP60 levels increase gradually through
carcinogenic steps (from PIN to carcinoma) of
prostate (Cappello et al., 2003b).
Exocervical cancer
Note
Exocervical cancer is preceded by the so called
'squamous intraepithelial lesion' or SIL, a dysplastic
(pretumoral) lesion (Garrett and McCann, 2013).
SIL, as well as exocervical cancer, have been related
to infection by Human Papilloma Virus (HPV)
(Garrett and McCann, 2013).
Disease
Hsp60 levels are increased in exocervical cancer, as
shown by immunohistochemistry (Cappello et al.,
2002-2003; Castle et al., 2005).
Oncogenesis
HSP60 levels increase gradually through
carcinogenic steps (from SIL to carcinoma) of
exocervix (Cappello et al., 2002-2003).
Vesical cancer
Disease
HSP60 levels are decreased in vesical cancers such
as bladder carcinoma (Lebret et al., 2003; Cappello
et al., 2006b).
Prognosis
HSP60 is considered a useful marker for patients
with superficial bladder carcinoma for predicting
disease progression: lower levels correlate with
worse outcome of local treatments. Particularly,
HSP60 levels are considered useful prognostic
marker to identify patients for whom local treatment
HSPD1 (Heat Shock 60kDa Protein 1) Cappello F, et al.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9) 584
would be insufficient (Lebret et al., 2003). Hsp60
levels may predict response to neoadjuvant
chemoradiotherapy in invasive or high-risk
superficial bladder cancer (Urushibara et al., 2007).
To be noted HSP60 may participate in the process of
carcinogenesis, representing cases of
chaperonopathies by mistake or collaborationism in
which a normal chaperone (at least considering the
methods available nowadays to characterize
intracellular molecules, or extracellular molecules at
very low concentrations) contributes to cancer
development (Macario et al., 2013).
HSP60 may participate also in the process of chronic
inflammation (Cappello et al., 2011b) and
autoimmune diseases (Cappello et al., 2009), also by
molecular mimicry phenomena. For example,
atherosclerosis has been postulated to be an
autoimmune disease due to an immune reaction
against heat-shock protein 60 (Wick et al., 2014).
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This article should be referenced as such:
Cappello F, Conway de Macario E, Macario AJL. HSPD1 (Heat Shock 60kDa Protein 1). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(9):575-585.