The family of mammalian small heat shock proteins (HSPBs): Implications in protein deposit diseases and motor neuropathies

doi:10.1016/j.biocel.2012.03.011

The International Journal of Biochemistry & Cell Biology

Volume 44, Issue 10, October 2012, Pages 1657-1669

https://doi.org/10.1016/j.biocel.2012.03.011 Get rights and content

Abstract

A number of neurological and muscular disorders are characterized by the accumulation of aggregate-prone proteins and are referred to as protein deposit or protein conformation diseases. Besides some sporadic forms, most of them are genetically inherited in an autosomal dominant manner, although recessive forms also exist. Although genetically very heterogeneous, some of these diseases are the result of mutations in some members of the mammalian small heat shock protein family (sHSP/HSPB), which are key players of the protein quality control system and participate, together with other molecular chaperones and co-chaperones, in the maintenance of protein homeostasis. Thus, on one hand upregulation of specific members of the HSPB family can exert protective effects in protein deposit diseases, such as the polyglutamine diseases. On the other hand, mutations in the HSPBs lead to neurological and muscular disorders, which may be due to a loss-of-function in protein quality control and/or to a gain-of-toxic function, resulting from the aggregation-proneness of the mutants. In this review we summarize the current knowledge about some of the best characterized functions of the HSPBs (e.g. role in cytoskeleton stabilization, chaperone function, anti-aggregation and anti-apoptotic activities), also highlighting differences in the properties of the various HSPBs and how these may counteract protein aggregation diseases. We also describe the mutations in the various HSPBs associated with neurological and muscular disorders and we discuss how gain-of-toxic function mechanisms (e.g. due to the mutated HSPB protein instability and aggregation) and/or loss-of-function mechanisms can contribute to HSPB-associated pathologies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

Section snippets

Structure of the sHSP superfamily

Small heat shock proteins (sHSPs) all contain a highly conserved sequence of 80–100 amino acids called the α-crystallin domain. This structural domain is responsible for many intra- and inter-molecular interactions leading to the formation of dimers, which are considered as the basic unit of sHSP (Van Montfort et al., 2001a, Van Montfort et al., 2001b, Kim et al., 1998). These dimers can interact with each other forming higher molecular weight oligomers. Besides the α-crystallin domain, both

Biochemical function(s) of the sHSPs/HSPBs

Currently, two main biochemical functions have been attributed to the small HSPs: the ability to stabilize the cytoskeleton and the chaperone-like activity (first characterized for the Archea, yeast and plant small HSPs). Another function that has been well-characterized for some members of the small HSP family is the anti-apoptotic activity that will be briefly summarized here (see Table 1).

HSPBs and protein deposit diseases

The potential protective function of the HSPBs in protein deposit disease has been addressed by evaluating the ability of the overexpressed HSPBs to inhibit the aggregation of several disease-associated proteins and protect cells from the aggregate-prone protein-mediated toxicity. Among the disease-related proteins used are mutated polyglutamine proteins, including mutated huntingtin, associated with Huntington disease (HD), mutated ataxin-3, associated with Spinocerebellar ataxia type 3

Mutations in HSPBs are associated with neuronal and muscular disorders

So far mutations in five members of the HSPB family, namely HSPB1, HSPL27/HSPB3, HSPB4, HSPB5 and HSPB8, have been associated with the development of neurological and muscular disorders. In particular, mutations in HSPB1, HSPB3 and HSPB8 are associated with Hereditary Peripheral Neuropathies (HPNs) (Evgrafov et al., 2004, Irobi et al., 2004, Kolb et al., 2010), while mutations in HSPB4 and HSPB5 are associated with either Congenital Cataract (CC; HSPB4) or both CC and myofibrillar myopathies

HSPBs and hereditary peripheral neuropathies

Mutations in HSPB1, HSPB3 and HSPB8 are associated with the development of hereditary peripheral neuropathies (HPNs).

HSPBs and congenital cataract

Mutation in HSPB4 and HSPB5 are associated with congenital cataract.

Myofibrillar myopathies: classification, characteristics and etiology

Myofibrillar myopathies (MFMs) are a group of chronic neuromuscular diseases genetically distinct and usually transmitted by autosomal dominant inheritance, although a few rare X-linked and autosomal recessive forms exist as well. MFMs are characterized by slowly progressive weakness of both proximal (frequency of 25%) and distal (frequency of 80%) muscles. Peripheral neuropathy and overt cardiomyopathy are present in about 15–30% of affected individuals. MFMs consist of myofibrillar

Conclusions and remarks

The mammalian family of small heat shock proteins (sHSP/HSPB) consists of ten members (HSPB1–HSPB10), which are characterized by different functions and display different expression profiles (with some members being ubiquitously expressed, like e.g. HSPB1, HSPB5 and HSPB8 and some other members being expressed exclusively in one cell type/tissue, like e.g. HSPB9 and HSPB10 that are only found in testis). While some members exert mainly refolding activities and have very poor or no

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^☆: This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

¹: These authors equally contributed to the manuscript.

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The family of mammalian small heat shock proteins (HSPBs): Implications in protein deposit diseases and motor neuropathies☆

Abstract

Section snippets

Structure of the sHSP superfamily

Biochemical function(s) of the sHSPs/HSPBs

HSPBs and protein deposit diseases

Mutations in HSPBs are associated with neuronal and muscular disorders

HSPBs and hereditary peripheral neuropathies

HSPBs and congenital cataract

Myofibrillar myopathies: classification, characteristics and etiology

Conclusions and remarks

J Biol Chem

Am J Hum Genet

Free Radic Biol Med

J Biol Chem

Neuron

J Biol Chem

J Biol Chem

J Biol Chem

Blood

J Biol Chem

Eur J Cell Biol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Neurol Sci

Biochem Biophys Res Commun

J Biol Chem

Curr Biol

J Biol Chem

J Biol Chem

Arch Biochem Biophys

J Biol Chem

Trends Cell Biol

J Biol Chem

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

Invest Ophthalmol Vis Sci

J Neurol Sci

A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes

Hum Mol Genet

Small heat-shock protein hspb1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy

J Neurosci

Transduced HSP27 protein protects neuronal cell death by enhancing FALS-associated SOD1 mutant activity

BMB Rep

Hsp27: novel regulator of intracellular redox state

IUBMB Life

The cellular networking of mammalian Hsp27 and its functions in the control of protein folding, redox state and apoptosis

Adv Exp Med Biol

Hsp27 consolidates intracellular redox homeostasis by upholding glutathione in its reduced form and by decreasing iron intracellular levels

Antioxid Redox Signal

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

Hum Mol Genet

Structure and function of the conserved domain in alphaA-crystallin. Site-directed spin labeling identifies a beta-strand located near a subunit interface

Biochemistry

Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila

PLoS Genet

Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2

Nat Genet

Mutation R120G in alpha B-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function

Proc Natl Acad Sci U S A

Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin

Proc Natl Acad Sci U S A

Differential binding of mutant (R116C) and wildtype alphaA crystallin to actin

Curr Eye Res

Hsp27 negatively regulates cell death by interacting with cytochrome c

Nat Cell Biol

Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo

Oncogene

Regulation of stress-induced intracellular sorting and chaperone function of Hsp27 (HspB1) in mammalian cells

Biochem J

Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

Nature

HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells

Hum Mol Genet