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The heat shock response is characterized by a rapid and robust increase in heat shock proteins upon exposure to protein-damaging stresses. This evolutionarily conserved cellular protection mechanism is primarily regulated at the level of transcription. In bacteria, heat shock-induced transcription is regulated by the activation of factor, whereas eukaryotes utilize heat shock transcription factors (HSFs) that bind to specific heat shock elements (HSEs) within the promoters of their target genes. Unlike yeasts, nematodes, and fruit flies, which have a single HSF, vertebrates and plants have an entire HSF family. In addition to stress-induced activation, some members of the HSF family are also activated under non-stressful conditions, including development and differentiation. The activity of HSFs is under post-translational control, requiring trimerization, DNA binding, and hyperphosphorylation. The interplay between different family members and other interacting proteins adds further complexity to HSF-mediated transcription. Here, we summarize the current knowledge of the transcriptional regulation of the heat shock response, highlighting recent advances in exploring the multi-faceted nature of heat shock transcription.

As a key organelle of protein targeting and secretion, the endoplasmic reticulum (ER) plays host to a wide variety of protein maturation steps including folding, modification, and complex formation. Homeostasis of ER function is therefore critical to cell function. The unfolded protein response (UPR), a conserved eukaryotic signal transduction pathway, regulates the ER’s capacity to perform protein folding according to cellular demand. UPR signaling is initiated by ER transmembrane components that sense unfolded protein levels within the ER. In yeast, the only known UPR initiator is IRE1, a transmembrane serine/threonine kinase/ endoribonuclease. In higher eukaryotes, the UPR also comprises signals initiated by the ER-transmembrane kinase PERK and the ER-transmembrane transcription factor ATF6. A major consequence of UPR initiator activation is transcription induction of a wide variety of genes for ER-resident chaperons and protein folding enzymes, in order to increase ER protein folding capacity. Ultimately, UPR activation leads to remodeling the entire secretory pathway in order to meet cellular demand. The identification of these initiators and recent studies of their behaviors is revealing fascinating aspects of the overall UPR. This review discusses highlights of these discoveries and relationships between the UPR signaling branches initiated by each ER component.

All newly synthesized proteins must fold to their correct native conformation in order to function. That protein folding in the crowded macromolecular environment of the cell is as efficient as it appears to be is remarkable in itself. However, physical or chemical stresses or the accumulation of aberrant proteins encoded by mutated genes can easily perturb protein folding homeostasis in cells. In the protein biochemistry laboratory the aggregation of proteins can be frustrating and even aggravating, but when partially folded or misfolded proteins aggregate in the cell or even, in the case of systemic amyloidoses or Alzheimer’s Disease, outside the cell, the consequences can be devastating. Molecular chaperones typically play a key role in preventing protein aggregation. However, this monograph describes the biology and biochemistry of yeast Hsp104p, an unconventional molecular chaperone that specializes, not in preventing, but in reversing protein aggregation.

The endoplasmic reticulum (ER) is a membranous compartment that can be found within any nucleated eukaryotic cell. Its job is to oversee the production of all the proteins that the cell secretes, or needs to express at the cell surface or within the secretory pathway itself. The type of proteins that pass through the ER is very varied, ranging from small, secreted peptide hormones, to large cell surface receptors. To the uninitiated, protein folding in the endoplasmic reticulum might seem straightforward. Unfortunately for biology students, but fortunately for researchers, it turns out that protein folding in the ER is a complex business, involving chaperones, quality control machinery and many accessory factors. These molecular helpers make sure that glycoproteins fold properly, and are directed to the right cellular location at the right time. Although many newly synthesised proteins follow a set of common ”rules”, some proteins require specific types of chaperones to assist them. In this review, recent advances in our knowledge of the early stages of ER protein folding will be discussed, focusing on the mammalian ER, but also drawing on examples of work in yeast.

The quality control of proteins within mitochondria is ensured by conserved and ubiquitous ATP-dependent molecular chaperones and proteases, present in various subcompartments of the organelle. Hsp70 chaperones drive protein import and facilitate folding of newly imported preproteins, but are also required for proteolysis of misfolded polypeptides by ATP-dependent proteases. Energy dependent proteases in mitochondria include Lon and Clp proteases in the matrix space and two AAA proteases in the inner membrane, all of them compartmental proteases of the AAA family with chaperone-like properties. Studies in yeast identify essential regulatory roles of these proteases for mitochondrial genome integrity, gene expression, the assembly of the respiratory chain, and mitochondrial morphology. An impaired proteolytic system in mitochondria has been identified as a cause for neurodegeneration in human. The present review summarizes the current understanding of the protein quality system in mitochondria and discusses the molecular action of protein machineries involved.

Peroxisomes are ubiquitous organelles present in most eukaryotic cells. Their role in cellular metabolism is diverse among species. An array of genes involved in the formation and maintenance of peroxisomes has been discovered, and can be categorised into genes important for protein import into the peroxisome and genes involved in the maintenance of the organelles’ size and abundance. Thorough cell biological and biochemical studies revealed great detail about the process of peroxisomal protein import. Although involvement of several classes of molecular chaperone proteins in peroxisomal protein import has been demonstrated, details regarding the mechanistic aspects of chaperone involvement in this process are not known yet. This review aims to discuss peroxisomal maintenance, with the emphasis on protein import. A general overview of chaperone proteins and their role in protein import processes will be used as context to discuss the – possible – roles of chaperone proteins in peroxisomal protein import.

One of the most important functions of cellular quality control systems is to maintain structural fidelity of proteins. Molecular chaperones prevent aggregation and assist folding of newly synthesized proteins in the cytosol and the ER. Furthermore, in concert with ubiquitin-ligases, chaperones detect misfolded or damaged proteins and target them for degradation by the ubiquitin-proteasome system. Some ligases link recognition of aberrant cytosolic proteins to degradation. In degradation of malfolded secretory proteins from the ER, recognition by chaperones is separated from the ubiquitin-proteasome system by the ER-membrane. Therefore, dislocation precedes ubiquitination mediated by two -finger ligases in the ER membrane. Proteins are marked for degradation by the attachment of poly-ubiquitin chains. Poly-ubiquitinated proteins are subsequently recognized by a Cdc48p/p97 complex and delivered to the proteasome where they are degraded. Malfunction of protein degradation by the ubiquitin-proteasome system leads to the generation of severe human diseases.

Proteins with prion properties are closely associated to a class of fatal neurodegenerative illnesses in mammals and to the emergence and propagation of phenotypic traits in yeast. The structural transition from the correctly folded, native form of a prion protein to a persistent misfolded form that ultimately may cause cell death or the transmission of phenotypic traits are not yet fully understood. The structural and functional properties of mammalian and yeast prions in their soluble and oligomeric forms are presented as are the mechanistic models accounting for this structure-based mode of inheritance. This review highlights a number of unquestioned issues and unanswered questions that may allow a better understanding of the role of prion proteins and their propagation mechanism(s).

The Hsp60 molecular chaperones (the chaperonins) are essential proteins throughout biology. They can be separated into two evolutionary classes: the Group I chaperonins from eubacteria and their endosymbiotic counterparts in eukaryotic cells, and the Group II chaperonins from archaea and the eukaryotic cytosol. While the two classes have some similarity to each other in structural and functional characteristics, they also have a number of important distinctions implying that they may have some significant differences in their modes of action. In this review we first examine our current understanding of the Group I class, typified by GroE from , before looking at the recent developments in the much less well-studied Group II chaperonins, including the archeal thermosome and eukaryotic CCT.