Partners in surveillance and quality control: G. L. Blatch (ed): Networking of chaperones by co-chaperones. 2007, Landes Bioscience/Eurekah.com and Springer Science+Business Media, LLC, ISBN: 978-0-387-49308-4

Cellular proteins need varying degrees of instruction and assistance during their appearance in the cell and in conducting their activities. They also have to bow out of the job at the appropriate time. Key figures in the control of protein expression and homeostasis are the molecular chaperones. Many of these proteins are essential to all cells and they serve a number of different purposes. They usually work together as chaperone machines to assist in the processes of protein folding, the repair of improperly folded proteins, the degradation of unwanted proteins, and in some cases, the stabilization and control of key cell regulators. Within these chaperoning processes, important decisions must be made. Upon handling of a difficult client, some component of the chaperone machine must determine when to pass off a client to another system, direct the client toward degradation, or simply try it again. Thus, client proteins must be selected and sorted in various ways. To fulfill these tasks, most chaperone systems are aided by a number of cochaperones—proteins that add additional information or a specialized function to the chaperoning system. Cochaperones add much diversity to chaperone machines, and a growing number of proteins in this category are being recognized. “Networking of chaperones by co-chaperones” is the first published volume dedicated solely to cochaperones. This is a timely addition and perhaps overdue since this field has grown dramatically over the past 10–15 years. This volume contains 11 chapters on separate topics contributed by authorities in the field. The chapters are surprisingly similar in quality and design, which is a credit to its editor, Gregory Blatch. Each contains a brief, but very informative introduction to the topic; an excellent aid for newcomers to the field. This is followed by an update on our current knowledge on the subject. This is also quite brief, but very informative with excellent reference to the literature. This reviewer found all of the chapters to be very readable and thought-provoking. Although knowledge on all cochaperone systems is still incomplete, the systems selected for this volume are somewhat advanced and biased toward the Hsp70 and Hsp90 chaperone pathways. Seven of the chapters concern cochaperones for the Hsp70 family. Abundant chaperones of the Hsp70 family exist in all cell compartments and are needed for many routine activities such as the folding of nascent proteins, the transport of proteins through membranes, the uncoating of clathrin-coated vesicles, the assembly of multisubunit proteins, and the transport of proteins to the proteasome for degradation This system is complex with a confusing number of J protein cochaperones (Hsp40s) and nucleotide exchange factors (NEFs). These are needed to support the ATP-dependent Hsp70 chaperoning cycle. This chaperone network is clearly predominant and essential for cell viability, and there is little overlap among the chapters. Little was known about eukaryotic NEFs until recently, but some have emerged (Bag1, HspBP1) with quite curious properties (J. Brodsky and A. Bacher). Rather than simply accelerating the Hsp70 cycle, their roles may be more regulatory and they may promote or inhibit a particular chaperoning event. Numerous Hsp40 proteins have been identified (M.F.N. Rosser and D.M. Cyr). While they stimulate the Hsp70 cycle though their J domains, their roles in client recognition and their possible chaperoning functions on their own are actively being investigated. A chapter on the ER compartment concerns mainly the Hsp70 family and their Hsp40 and NEF cochaperones (J. Dudek et al.). Much remains unknown in this complex system as to the way these proteins interact with one another and their functional roles, other than in protein import. The Hsp70 systems are also the focus in the mitochondria (D. Bursac and T. Lithgow). While the useful analogies to bacterial chaperoning are evident, mitochondria require additional chaperoning machinery, particularly for protein import. Of the many cochaperones for Hsp90, four very distinct groups were included in this volume. The first concerns the large FKBP immunophilins (M.B. Cox and D.F. Smith). These were identified early and much is known on their structures and biological importance. However, their mechanisms of action still remain vague. Similar statements can be made for Cdc37, the first Hsp90 cochaperone to be recognized (A.J. Caplan). While this protein is essential for the chaperoning of protein kinases, its functions in relation to the other components of the chaperone machine remain unclear. The cochaperone UNC-45 (O.O. Odunuga and H.F. Epstein) is in a novel group of proteins having “UCS” domains which are involved in the chaperoning of myosins, and UNC-45 impacts many cellular processes such as muscle function, development, and cytokinesis. A more thoroughly studied protein, Hop, is a cochaperone for both Hsp70 and Hsp90 and it appears to coordinate their functions (S. Daniel et al.). However, recent observations on the interaction of Hop with additional proteins and the changes in its phosphorylation and cellular localization suggest more expanded roles for this protein. Of the remaining chapters, there is one chapter on GroES, the cochaperone for GroEL (H. Liu and P.A. Lund). GroES is the best understood cochaperone in terms of structure/function relationships, but there are still many unknowns, most notably with homologous systems in cell organelles. The last two chapters are particularly thought-provoking since they are on subjects that are very incomplete but are growing rapidly. Chapter 10 is on the link between chaperones and the ubiquitin/proteasome degradation system (J. Hohfeld et al.). While chaperone functions clearly support this system, much remains unknown on the cochaperone participants and the principles that dictate the fate of client proteins. The final chapter addresses our knowledge on chaperones and protein folding diseases (J. van der Spuy et al.). This topic is at a more descriptive phase that has focused mainly on Hsp70. However, some interesting examples are noted which correlate mutations in chaperones or cochaperones to disease states. There are no weak chapters in this volume and it is highly recommended for both newcomers and senior investigators in this field. Perhaps, its only significant shortcoming is that it could easily have been expanded to two or three times its size and scope. We now know of many chaperone systems that are important to various cellular processes and each has a battery of supporting cochaperones. For examples, there are about two dozen known cochaperones that just serve the Hsp90 machine, and full coverage would be too much to ask and probably would not be desirable. Perhaps a sequel on the subject will be considered. While this volume is available in hard copy, the chapters may also be obtained from the Eurekah Bioscience Database at Eurekah.com.