Stress response pathways: machineries and mechanisms

Cells contain thousands of different proteins which carry out and coordinate all functions of life. During cell growth, but also in non-dividing cells, proteins have to be synthesized, folded and assembled with other proteins or with co-factors; proteins which do not reside in the cytosol have in addition to be translocated across membranes (Figure 1). Proteins which fail in any of these steps need to be recognized and removed by degradation or sequestration to prevent harmful, proteotoxic consequences. Over the last years, the processes which coordinate and control the quality of protein biogenesis have been studied in depth and many of the underlying mechanisms could be unraveled. New quality control factors that ensure protein homeostasis (proteostasis) were discovered and their structures, biochemical functions and physiological relevance were elucidated. These factors include molecular chaperones and components of the protein-degrading protease machineries. Excellent review articles had been published on the processes of protein folding and protein degradation (Dikic 2017; Hipp et al. 2019; Sontag et al. 2017).

Figure 1:

The biogenesis of functional proteins depends on their translocation, folding and assembly. Problems in these processes lead to the accumulation of non-native proteins which triggers stress response pathways allowing cells to respond to these problems, for example by changes in the expression of genes and the synthesis of proteins in the cytosol. This highlight issue of Biological Chemistry comprises 12 review articles which provide a comprehensive overview of the molecular processes maintaining proteostasis even upon stress-inducing challenges.

This highlight issue of Biological Chemistry contains a collection of review articles which cover different aspect of the cellular proteostasis system with a specific emphasis on pathways that allow cells to remodel their proteomes upon proteotoxic conditions. These stress conditions, such as high temperature, mitochondrial dysfunction or oxidative challenges, induce complex regulatory networks that allow cells to cope with these challenges and to acquire stress resistance. Notably, these stress-responsive systems are evolutionary conserved but evolved further in complexity with the advent of multi-cellular organisms inducing changes of many biological processes. In a nutshell, stress response reactions involve two central cellular processes (Figure 1). They change the levels of gene expression in order to remodel the proteome: the transcription of genes encoding quality control factors such as chaperones is typically upregulated under such conditions, whereas the transcription of other genes is often reduced. These changes on the transcription levels are referred to as heat shock response or oxidative stress response, dependent on the initial stress-inducing problem (Ali et al. 2024; Hastbacka et al. 2025; Sies et al. 2017). As a second layer of response, the overall level of protein synthesis in the cytosol is typically reduced upon stress conditions, a strategy that it also referred to as the integrated stress response (Costa-Mattioli and Walter 2020). Despite the reduction in translation, the synthesis of individual proteins, such as chaperones, can still occur at high levels under such conditions.

High temperatures impair the folding of proteins and destabilizes protein structures. How stress responses can be studied comprehensively is outlined in the article by Felix Jung, David Zimmer and Timo Mühlhaus (Jung et al. 2025). The response to temperature changes is particularly important for plants. In their article, Sotirios Fragkostefanakis, Enrico Schleiff and Klaus-Dieter Scharf provide an overview on the heat shock response of plant cells (Fragkostefanakis et al. 2025). Under conditions of proteotoxic stress, unfolded proteins accumulate in the unicellular alga Chlamydomonas reinhardtii. Strategies to react to these increased levels are described in the overview article by Sarah Gabelmann and Michael Schroda (Gabelmann and Schroda 2025). Plant cells have a very powerful response program against oxidative stress as outlined by José Ugalde, Manjeera Nath, Stephan Wagner and Andreas Meyer (Ugalde et al. 2025). Oxidative stress can also be a challenge for mammalian cells; in their article Johannes Ebding, Fiorella Mazzone, Stefan Kins, Jan Pielage and Tanja Maritzen explain how neurons react to oxidizing conditions (Ebding et al. 2025).

Mitochondria are essential organelles of eukaryotic cells. They consist of about 1,000 different proteins, most of which are synthesized as precursors in the cytosol from where they are imported into mitochondria. The accumulation of precursor proteins can strongly challenge cellular proteostasis as explained in the article by Nikolaos Charmpilas, Qiaochu Li and Thorsten Hoppe using the nematode Caenorhabditis elegans as model system (Charmpilas et al. 2025). The cytosol can sequester precursor proteins in structures called MitoStores; how these structures protect cells against the proteotoxic consequences of precursors is described by Pragya Kaushik, Johannes Herrmann and Katja Hansen (Kaushik et al. 2025). If precursor proteins are not efficiently imported into mitochondria, they can clog the import machinery; to prevent this, ubiquitin ligases and other quality control factors are recruited to the mitochondrial surface as described by Joshua Jackson and Thomas Becker (Jackson and Becker 2025). The intermembrane space, i.e. the compartments between the outer and inner membrane of mitochondria, is particularly sensitive to proteotoxic conditions; how this compartment can keep its proteome balanced and functional is explained by Matthias Weith, Konstantin Weiss, Dylan Stobbe and Jan Riemer (Weith et al. 2025).

Chaperones are key elements in the protection against proteotoxic stress. They act already early during protein synthesis to avoid the misfolding of nascent polypeptide chains. In their review, Laurenz Rabl and Elke Deuerling describe the biology of the nascent chain-associated complex NAC which binds near the protein exit site of the ribosome to coordinate the processing and folding steps of nascent chains as soon as they emerge (Rabl and Deuerling 2025). The Hsp90 chaperone, together with its multiple co-chaperones, arguably represent the most complex chaperone network which is of importance for the folding of complex proteins. Sonja Engler and Johannes Buchner provide a comprehensive overview of the players of this system and the evolution of the system from yeast to mammals (Engler and Buchner 2025). Aneuploidy, the presence of additional chromosomes which is frequently observed in cancer cells, challenges proteostasis owing to the imbalance in gene expression as described by Prince Amponsah and Zuzana Storchová (Amponsah and Storchova 2025).

Together, this collection of reviews provides an excellent overview of this exciting area of research and its future directions. Ideally, it will also stimulate young researchers to join this field.