Thermotolerance in mammalian cells. Protein denaturation and aggregation, and stress proteins

Cells that have been pre-exposed to thermal stress can acquire a transient resistance against the killing effect of a subsequent thermal stress. The cause for this phenomenon, called thermotolerance, seems to be an enhanced resistance of proteins against thermal denaturation and aggregation. This resistance can be expressed as an attenuation of damage formation (less initial damage) or as a better repair of the protein damage (facilitated recovery). Heat Shock (or better, Stress) Proteins (HSPs) may play a role in and even be required for thermal resistance. However, rather than stress-induced enhanced synthesis and elevated total levels of HSPs per se, the concentration of, both constitutive and inducible, HSPs at and/or (re)distributed to specific subcellular sites may be the most important factor for the acquisition of thermotolerance. Specific HSPs may be involved either in damage protection or in damage repair

DNAJs:more than substrate delivery to HSPA

Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process

Protein quality control:from mechanism to disease EMBO Workshop, Costa de la Calma (Mallorca), Spain, April 28-May 03, 2019

The cellular protein quality control machinery with its central constituents of chaperones and proteases is vital to maintain protein homeostasis under physiological conditions and to protect against acute stress conditions. Imbalances in protein homeostasis also are keys to a plethora of genetic and acquired, often age-related, diseases as well as aging in general. At the EMBO Workshop, speakers covered all major aspects of cellular protein quality control, from basic mechanisms at the molecular, cellular, and organismal level to medical translation. In this report, the highlights of the meeting will be summarized

The regulation of the autophagic network and its implications for human disease

Autophagy has attracted a lot of attention in recent years. More and more proteins and signaling pathways have been discovered that somehow feed into the autophagy regulatory pathways. Regulation of autophagy is complex and condition-specific, and in several diseases, autophagic fluxes are changed. Here, we review the most well-established concepts in this field as well as the reported signaling pathways or components which steer the autophagy machinery. Furthermore, we will highlight how autophagic fluxes are changed in various diseases either as cause for or as response to deal with an altered cellular homeostasis and how modulation of autophagy might be used as potential therapy for such diseases

Digest it all:the lysosomal turnover of cytoplasmic aggregates

Aggrephagy describes the selective lysosomal transport and turnover of cytoplasmic protein aggregates by macro-autophagy. In this process, protein aggregates and conglomerates are polyubiquitinated and then sequestered by autophagosomes. Soluble selective autophagy receptors (SARs) are central to aggrephagy and physically bind to both ubiquitin and the autophagy machinery, thus linking the cargo to the forming autophagosomal membrane. Because the accumulation of protein aggregates is associated with cytotoxicity in several diseases, a better molecular understanding of aggrephagy might provide a conceptual framework to develop therapeutic strategies aimed at delaying the onset of these pathologies by preventing the buildup of potentially toxic aggregates. We review recent advances in our knowledge about the mechanism of aggrephagy

Barcoding heat shock proteins to human diseases: looking beyond the heat shock response

There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR)--and thus generally restoring the disturbed protein homeostasis associated with such diseases--has often been suggested as a therapeutic strategy. However, most data on activating the HSR or its downstream targets in mouse models of diseases associated with aggregate formation have been rather disappointing. The human chaperonome consists of many more heat shock proteins (HSPs) that are not regulated by the HSR, however, and researchers are now focusing on these as potential therapeutic targets. In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation. Some of these 'non-canonical' HSPs have demonstrated effectiveness in vivo, in mouse models of protein-aggregation disease. Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review