Small Stress Proteins

Edited by:
  • A. P. Arrigo &
  • W. E. G. Müller
Springer Verlag, 2002 Hardback,£90.50/$139

Heat shock and other stresses induce the expression of several families of proteins. In turn, these heat shock proteins (HSPs) protect cells against the consequences of these agressions. One of these families is the small HSP family. Proteins from this family range in monomer size from 12–48K, are characterized by a conserved α-crystallin domain in their C-terminal part and form oligomeric stuctures ranging from 9–50 subunits. Most small HSPs are efficient chaperones. They interact with intermediate filaments and the actin cytoskeleton, modulate intracellular oxidative stress and prevent apoptotic cell death. As these chaperones have been identified later than the other HSP families, small HSPs have been referred as the 'forgotten chaperones'. The book edited by A. P. Arrigo and W. E. G. Müller, the first one specifically devoted to these proteins, now corrects this omission. The fourteen chapters provide a large overview of current knowledges concerning the evolution, structure, expression and functions of small HSPs in different organisms, from prokaryotes to human. Finally, the only chaperones that remain forgotten are plant small HSPs, which are not included in this book.

The evolutionary history of small HSPs, studied in prokaryotes, the desert fish Poeciliopsis lucida, the nematode Caenorrhabditis elegans, the fly Drosophila melanogaster and various mammals, provides some clues on the structural relationships of α-crystallin domain proteins. Interestingly, certain bacteria seem to do without small HSPs, whereas other prokaryotes contain up to 12 small HSP genes. Some prokaryotic small HSPs function as chaperone-like proteins in the cytoplasm whereas others have become structural components of the spore coat. This functional diversity may account for the variety of these proteins. Analysis of the developmental expression pattern of small HSPs in various tissues demonstrates a complex and coordinated regulation in both non-mammals and mammals. This developmental regulation occurs primarily at the level of transcription, but seems to be independent of heat shock transcription factors (HSFs) and their heat shock element (HSE) target-sequence; for example the developemental expression of Drosophila small HSPs is regulated mainly by steroid hormones, whereas hormone-regulated mammalian HSP27 expression is limited to specific tissues in mammals.

Of the seven identified mammalian small HSPs, only αB-crystallin and HSP27 are stress-inducible and this regulation is believed to be controlled mainly by HSF transcription factors. Post-translational modifications are essential regulators of their functions. They include mainly oligomerization and phosphorylation at specific serine residues. Both events can be related, at least in vitro, as phosphorylation of HSP27 triggers the conversion of the aggregated form (>500K) of the proteins into a dissociated form (<100K). However, cell–cell contacts enforce the formation of large oligomers, whatever the phosphorylation state of the protein. Several pathways lead to small HSP phosphorylation with a central function for MAPKAP kinase-2/-3. These, and other post-translational modifications, modulate the functions of HSPs.

One of the main functions of small HSPs is their ability to behave as molecular chaperones. This property does not depend on ATP supply and is associated with the formation of large oligomers, at least in mammal cells. Thus, small HSPs bind several non-native proteins per oligomeric complex, therefore representing the most efficient chaperone family in terms of the quantity of substrate binding. Another important property of the small HSPs is to participate in the maintenance and control of the cytoskeleton by interacting with intermediate filaments and actin, which leads to the exciting hypothesis of the chaperone–cytoskeleton complex as the guardian of the cytoplasm in stressed cells.

A more recent area of investigation concerns the protective effect of mammalian small HSPs against cell death, which may account for many functions of these proteins during development, cell differentiation, the response to stress and tumorigenesis. In the book, this protective effect is somewhat artificially divided in two parts. The first part deals with intracellular redox state modulation whereas the other distinguishes a post-mitochondrial role through specific interaction with cytochrome c when released in the cytosol, and a premitochondrial effect that requires higher HSP27 expression levels. Despite these protective properties, the prognostic value of HSP27 expression in human tumors remains controversial.

Finally, a physiological role for small HSPs has been identified in several human diseases. Two mutations cause autosomal dominant cataract formation and, interestingly, one of them is also the genetic basis of a cardiomyopathy. The effect of the latter mutation is very similar to that caused by a desmin mutation, suggesting the importance of small HSP interactions with the intermediate filament network in cardiac cells. In the nervous system, small HSP expression is normally limited to well-defined subsets of neurons but increases in neurodegenerative diseases, although the consequences of this overexpression remain a matter of speculation. The book ends with a plea for a more extensive analysis of the protective properties of HSP27 in vivo and anticipates potential therapeutic approaches in cardiac and cerebral ischaemia.

Several of the excellent contributions collected by A. P. Arrigo and W. E. G. Müller include unpublished data that reinforce the outstanding interest of their book. Researchers specifically involved in the field as well as those who deal with other aspects of cell biology will find here a reference. Obviously, many aspects of the in vivo functions of small HSPs remain to be clarified, but small HSPs will be no longer forgotten.