HSPBs: Small proteins with big implications in human disease

Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 06/2012; 44(10):1706-10. DOI: 10.1016/j.biocel.2012.06.005
Source: PubMed


Although initially somewhat ignored, recent studies have now clearly established that the diverse members of the human family of small HSPs (HSPB1-HSPB10) play crucial roles in a wide range of cell types to maintain the integrity and function of tissues, in particular that of nervous and muscular tissue. The 10 human HSPBs clearly have overlapping and non-overlapping functional characteristics. Their ability to self- and hetero-oligomerise provides the cells with a large array of potentially different, specific functions. Single HSPB members can have a multitude of functions (moonlighting) and act on different "clients", thus affecting a wide range of different processes or structures that can ultimately affect the rate of aging of tissues and entire organisms. This is underscored by the findings that some inherited diseases involve mutations in several HSPB members that cause premature (mostly muscle and neuronal) tissue degeneration. Inversely, cancer cell resistance to different anticancer therapies is associated with elevated expression of several HSPBs. Still, many unanswered questions exist about the precise functioning of HSPBs, their collaboration with other HSPB members as well as their functions within the entire cellular chaperone network. Also, better insight in the regulation of expression of the various members and how their function is modulated post-translationally is needed. Such may be crucially important to develop means to intervene with their function for therapeutic purposes, which would require functional down-regulation in cancer but up-regulation in, for instance, cardiac or degenerative neuro/neuromuscular diseases. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

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    • "In the cell, sHsps cooperate with members of the Hsp70/40 system for re-activation of their substrate proteins (Ehrnsperger et al., 1997; Haslbeck et al., 2005b; Lee et al., 1997; Mogk et al., 2003; Veinger et al., 1998). Due to this cyto-protective role, mutations in sHsps are implicated in a variety of diseases, such as cataract, neuropathies , and cancer (Kampinga and Garrido, 2012; Sun and MacRae, 2005). The most prominent sHsp, a-crystallin, is important for eye lens transparency and is also eponymous for the homology domain common to all sHsps (Horwitz, 2003). "
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    ABSTRACT: Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the aggregation of unfolding proteins during proteotoxic stress. In Caenorhabditis elegans, Sip1 is the only sHsp exclusively expressed in oocytes and embryos. Here, we demonstrate that Sip1 is essential for heat shock survival of reproducing adults and embryos. X-ray crystallography and electron microscopy revealed that Sip1 exists in a range of well-defined globular assemblies consisting of two half-spheres, each made of dimeric "spokes." Strikingly, the oligomeric distribution of Sip1 as well as its chaperone activity depend on pH, with a trend toward smaller species and higher activity at acidic conditions such as present in nematode eggs. The analysis of the interactome shows that Sip1 has a specific substrate spectrum including proteins that are essential for embryo development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 05/2015; 58(6). DOI:10.1016/j.molcel.2015.04.019 · 14.02 Impact Factor
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    • "In mammals , sHSPs are up - regulated in many different cancer cell types and are often linked to bad prognoses ( Boncoraglio et al . , 2012 ; Kampinga and Garrido , 2012 ) . The exact mechanisms by which Hsp22 operate in human cells has not been investigated deeply . "
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    ABSTRACT: Mitochondria are involved in many key cellular processes and therefore need to rely on good protein quality control (PQC). Three types of mechanisms are in place to insure mitochondrial protein integrity: reactive oxygen species (ROS) scavenging by anti-oxidant enzymes, protein folding/degradation by molecular chaperones and proteases and clearance of defective mitochondria by mitophagy. Drosophila melanogaster Hsp22 is part of the molecular chaperone axis of the PQC and is characterized by its intra-mitochondrial localization and preferential expression during aging. As a stress biomarker, the level of its expression during aging has been shown to partially predict the remaining lifespan of flies. Since over-expression of this small heat shock protein (sHSP) increases lifespan and resistance to stress, Hsp22 most likely has a positive effect on mitochondrial integrity. Accordingly, Hsp22 has recently been implicated in the mitochondrial unfolding protein response (mtUPR) of flies. This review will summarize the key findings on D. melanogaster Hsp22 and emphasis on its links with the aging process.
    Frontiers in Genetics 03/2015; 6. DOI:10.3389/fgene.2015.00103
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    ABSTRACT: The heat-shock protein 27 (HSP27) is up-regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.1-10 μg/ml) onto human microvascular endothelial cells (HMECs) grown as monolayers or spheroids. When added onto HMECs, rhHSP27 dose-dependently accelerates cell migration (with a peak at 5 μg/ml) and favors spheroid sprouting within 12-24 h. rhHSP27 increases VEGF gene transcription and promotes secretion of VEGF-activating VEGF receptor type 2. Increased VEGF transcription is related to NF-κB activation in 30 min. All of these effects are initiated by rhHSP27 interaction with Toll-like receptor 3 (TLR3). Such an interaction can be detected by immunoprecipitation but does not seem to be direct, as we failed to detect an interaction between rhHSP27 and monomeric TLR3 by SPR analysis. rhHSP27 is rapidly internalized with a pool of TLR3 to the endosomal compartment (within 15-30 min), which is required for NF-κB activation in a cytosolic Ca(2+)-dependent manner. The HSP27/TLR3 interaction induces NF-κB activation, leading to VEGF-mediated cell migration and angiogenesis. Such a pathway provides alternative targets for antiangiogenic cancer therapy.-Thuringer, D., Jego, G., Wettstein, G., Terrier, O., Cronier, L., Yousfi, N., Hébrard, S., Bouchot, A., Hazoumé, A., Joly, A.-L., Gleave, M., Rosa-Calatrava, M., Solary, E., and Garrido, C. Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3.
    The FASEB Journal 06/2013; 27(10). DOI:10.1096/fj.12-226977 · 5.04 Impact Factor
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