Protein folding in vivo is mediated by an array of proteins that act either as ‘foldases’ or ‘molecular chaperones’. Foldases include protein disulfide isomerase and peptidyl prolyl isomerase, which catalyze the rearrangement of disulfide bonds or isomerization of peptide bonds around Pro residues, respectively. Molecular chaperones are a diverse group of proteins, but they share the property that they bind substrate proteins that are in unstable, non-native structural states. The best understood chaperone systems are HSP70/DnaK and HSP60/GroE, but considerable data support a chaperone role for other proteins, including HSP100, HSP90, small HSPs and calnexin. Recent research indicates that many, if not all, cellular proteins interact with chaperones and/or foldases during their lifetime in the cell. Different chaperone and foldase systems are required for synthesis, targeting, maturation and degradation of proteins in all cellular compartments. Thus, these diverse proteins affect an exceptionally broad array of cellular processes required for both normal cell function and survival of stress conditions. This review summarizes our current understanding of how these proteins function in plants, with a major focus on those systems where the most detailed mechanistic data are available, or where features of the chaperone/foldase system or substrate proteins are unique to plants.

Molecular chaperones and protein folding in plants.

▪ Abstract A mechanism for regulating gene expression at the level of transcription utilizes an antagonist of the sigma transcription factor known as the anti-sigma (anti-σ) factor. The cytoplasmic class of anti-σ factors has been well characterized. The class includes AsiA form bacteriophage T4, which inhibits Escherichia coli σ70; FlgM, present in both gram-positive and gram-negative bacteria, which inhibits the flagella sigma factor σ28; SpoIIAB, which inhibits the sporulation-specific sigma factors, σF and σG, of Bacillus subtilis; RbsW of B. subtilis, which inhibits stress response sigma factor σB; and DnaK, a general regulator of the heat shock response, which in bacteria inhibits the heat shock sigma factor σ32. In addition to this class of well-characterized cytoplasmic anti-sigma factors, a new class of homologous, inner-membrane–bound anti-σ factors has recently been discovered in a variety of eubacteria. This new class of anti-σ factors regulates the expression of so-called extracytoplasmic fun...

The anti-sigma factors

Simian virus 40 (SV40) is a small DNA tumor virus that has been extensively characterized due to its relatively simple genetic organization and the ease with which its genome is manipulated. The large and small tumor antigens (T antigens) are the major regulatory proteins encoded by SV40. Large T antigen is responsible for both viral and cellular transcriptional regulation, virion assembly, viral DNA replication, and alteration of the cell cycle. Deciphering how a single protein can perform such numerous and diverse functions has remained elusive. Recently it was established that the SV40 T antigens, including large T antigen, are molecular chaperones, each with a functioning DnaJ domain. The molecular chaperones were originally identified as bacterial genes essential for bacteriophage growth and have since been shown to be conserved in eukaryotes, participating in an array of both viral and cellular processes. This review discusses the mechanisms of DnaJ/Hsc70 interactions and how they are used by T antigen to control viral replication and tumorigenesis. The use of the DnaJ/Hsc70 system by SV40 and other viruses suggests an important role for these molecular chaperones in the regulation of the mammalian cell cycle and sheds light on the enigmatic SV40 T antigen—a most amazing molecule.

T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis

Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential.

Successful viral infection requires viruses to redirect host biochemistry to replicate the viral genome, and produce and assemble progeny virions. Cellular heat-shock responses, which are characterized as elevation and relocalization of heat-shock proteins, occur during replication of many viruses1,2,3,4,5,6,7. Such responses might be host reactions to the synthesis of foreign protein, or might be irrelevant consequences of the viral need to activate transcription. Alternatively, as heat-shock proteins can facilitate protein folding8,9, activating a heat-shock response might be a specific virus function ensuring proper synthesis of viral proteins and virions. It is not possible to determine whether heat-shock response is essential for virus replication, because the implicated viral genes (such as Ad5 E1A, ref. 10) also control other essential replication steps. Here we report that expression of Gam1, a protein encoded by the avian virus CELO (ref. 11), elevates and relocalizes hsp70 and hsp40. Gam1-negative CELO is replication-defective; however, Gam1 function can be partially replaced by either heat shock or forced hsp40 expression. Thus, an essential function of Gam1 during virus replication is to activate host heat-shock responses with hsp40 as a primary target.

Activation of heat-shock response by an adenovirus is essential for virus replication.

The Escherichia coli/bacteriophage lambda genetic interaction system has been used to uncover the existence of various biological machines. The starting point of all these studies was the isolation and characterization of E. coli mutants that blocked lambda growth, and the corresponding lambda compensatory mutations. In this manner, the lambda N-promoted transcriptional anti-termination machine was discovered composed of the NusA/NusB/NusE/NusG host proteins. In addition, the DnaK and GroEL chaperone machines were discovered composed of DnaK/DnaJ/GrpE and GroES/GroEL heat shock proteins. The individual members of the DnaK and GroEL chaperone machines have been conserved throughout evolution in both function and structure. Their biological roles include a direct involvement in lambda DNA replication and morphogenesis, the protection of proteins from aggregation, the disaggregation of various protein aggregates, the manipulation of protein structure and function, as well as the autoregulation of the heat shock response. The evolution of lambda to extensively rely on the status of the heat shock response of E. coli is likely linked to its lytic versus lysogenic choice of lifestyle. The bacteriophage T4 gp31 protein has been purified and shown to substitute for many of GroES' co-chaperonin activities.

Alessandra Polissi

Papers

The Escherichia coli heat shock response and bacteriophage λ development