Molecular Biology of Small Heat Shock Proteins associated with Peripheral Neuropathies

Anne Holmgren, Neurogenetics Laboratory, Institute Born Bunge, Antwerpen, Belgium
Delphine Bouhy, Neurogenetics Laboratory, Institute Born Bunge, Antwerpen, Belgium
Vincent Timmerman, Neurogenetics Laboratory, Institute Born Bunge, Antwerpen, Belgium

Published online: November 2012

DOI: 10.1002/9780470015902.a0024294

Heat-shock proteins (HSPs) are molecular chaperones that protect the cell from various types of stress. Although regulated by stress, some of these proteins are constitutively expressed and responsible for quality control and protein folding. Based on their molecular weight, the HSP family mainly consists of two groups: large and small HSPs. The large HSPs require adenosine triphosphate (ATP) for their functioning, whereas the small HSPs (HSPBs) are ATP independent. The latter bind improperly folded proteins and assist in the targeting process for refolding or degradation. These HSPBs are not only molecular chaperones but they are also involved in many essential cellular processes such as apoptosis, autophagy, splicing, cytoskeleton dynamics and neuronal survival. This review focusses on the small HSPs HSPB1, HSPB3 and HSPB8, as mutations in these proteins are causative for Charcot–Marie–Tooth (CMT) disease and distal hereditary motor neuropathies (dHMN). Moreover, this review discusses the functional consequences of these mutations and their role in the length-dependent neurodegeneration typical of CMT diseases.

Key Concepts:

  • The molecular signature of the small HSPs is the conserved -crystallin domain.
  • Mutations in HSPB1, HSPB3 and HSPB8 are associated with dHMN and CMT subtypes.
  • Mutant HSPB1 causes instability of the cytoskeletal elements and therefore disorganisation of the neuronal cytoskeleton could underlie the peripheral neuropathies.
  • Mutant HSPB8 may induce pathomechanisms leading to CMT diseases through a loss of autophagy function, rather than a toxic gain of function.
  • The HSPB3 protein differs considerably from the other members regarding sequence similarity such as the poor conservation in the N-terminal region and the very short C-terminal domain.
  • It remains fragmentary how mutations in these small HSPs initiate a molecular cascade leading to progressive axonal degeneration.

Keywords: HSPB1; HSPB3; HSPB8; mutation; neurodegeneration; Charcot–Marie–Tooth disease; dHMN; apoptosis; autophagy

Figure 1. Schematic presentation of the HSPB1, HSPB3 and HSPB8 proteins. This scheme shows the different protein domains of the small HSPs HSPB1, HSPB3 and HSPB8, and the arrows indicate the neuropathy-associated mutations reported so far. The numbering refers to the amino acid residues delimiting the different protein domains. The HSPB1 protein is 205 amino acids long, has a monomeric mass of 27 kDa and contains both the amino-terminal WDPF and the C-terminal IXI/V motifs, which are well conserved among various HSPB members, and known to modulate the oligomerisation of the HSPB protein. The HSPB3 protein has a length of 150 amino acid residues and has a calculated monomeric mass of 17 kDa. Not much is known about this protein, nevertheless the almost complete absence of the C-terminal extension is a striking feature. Both HSPB3 and HSPB8 do not have a WDPF or IXI/V motif. The HSPB8 protein contains 196 amino acids and has a monomeric mass of 22 kDa. The -sheets 4 and 8 are indicated as they form the hydrophic groove, which is essential for the formation of the HSPB8-Bag3 complex. [P] , phosphorylation sites; ACD, -crystalline domain.
Figure 2. The HSPB1 protein interferes with the cell death signalling pathways at various levels. In the extrinsic apoptosis pathway, HSPB1 prevents translocation of death domain-associated protein G (Daxx) to the cytosol by interacting with it and thereby inhibiting the binding of Daxx to the Fas receptor and suppress Daxx-dependent apoptosis. Upstream of the mitochondrial release of cytochrome c, HSPB1 can activate the protective protein kinase Akt directly or through the phosphatidylinositol 3-kinase (PI3-K). Subsequently, Akt can prevent cytochrome c release through suppression of Bax mitochondrial translocation. At the same time, HSPB1 can inactivate the pro-death apoptosis-signal regulated kinase 1 (Ask1)–c-jun N-terminal kinase (JNK) pathway. Downstream of the mitochondrial release of cytochrome c, HSPB1 can directly interact with cytochrome c and therefore diminish the activation of procaspase-9, by inhibiting the proper formation of the apoptosome complex. But, it can also inhibit caspase-3 activity by interacting with the procaspase-3 molecule or by inhibiting the release of the mitochondria-derived activator of caspases (Smac/Diablo).
Figure 3. HSPB8 is involved in many different processes regulating the proteolytic degradation of unfolded proteins. The HSPB8 protein can stimulate the activity and affect the intracellular location of proteasomes and through this activate proteolytic degradation of certain proteins. More recently, HSPB8 was found to stimulate autophagy in a Bag3-dependent manner. Although HSPB8 is thought to be responsible for recognising misfolded proteins, Bag3 interacts with HSPA and modulates the targeting of client protein. Through the interaction with Bag3, HSPB8 becomes part of a multiheteromeric complex formed by HSPB8, Bag3, HSPA and the chaperone-associated ubiquitin ligase. The latter catalyses target proteins for ubiquitinylation and subsequent recruitment of the autophagic ubiquitin adaptor p62 leads to degradation of the misfolded proteins in autophagosomes, and thus autophagic removal. The HSPB8–Bag3 complex can also function independently of HSPA, as it was shown to lead to the phosphorylation of the -subunit of the translation initiator factor eIF2, which results in the stimulation of autophagy (Carra, 2009). The HSPB8–Bag3-mediated eIF2 phosphorylation was shown to be pancreatic endoplasmic reticulum kinase (PERK)- and phospholipase C-1-independent, leaving the upstream player(s) responsible for eIF2 phosphorylation unknown. However, part of the effects may be through the activation of the General control non-derepressible 2 kinase, and deletion of the PXXP domain of Bag3 affected the eIF2 phosphorylation, suggesting that the HspB8–Bag3 complex interacts through this domain with the unknown essential factor to modulate eIF2 phosphorylation.
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Related Sub-Topics:

Neurobiology of Disease | Protein Folding, Evolution and Degradation | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Molecular Biology of Small Heat Shock Proteins associated with Peripheral Neuropathies
 
How to Cite close
Holmgren, Anne, Bouhy, Delphine, and Timmerman, Vincent(Nov 2012) Molecular Biology of Small Heat Shock Proteins associated with Peripheral Neuropathies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024294]