The stress of protein misfolding: from single cells to multicellular organisms

Abstract

Organisms survive changes in the environment by altering their rates of metabolism, growth, and reproduction. At the same time, the system must ensure the stability and functionality of its macromolecules. Fluctuations in the environment are sensed by highly conserved stress responses and homeostatic mechanisms, and of these, the heat shock response (HSR) represents an essential response to acute and chronic proteotoxic damage. However, unlike the strategies employed to maintain the integrity of the genome, protection of the proteome must be tailored to accommodate the normal flux of nonnative proteins and the differences in protein composition between cells, and among individuals. Moreover, adult cells are likely to have significant differences in the rates of synthesis and clearance that are influenced by intrinsic errors in protein expression, genetic polymorphisms, and fluctuations in physiological and environmental conditions. Here, we will address how protein homeostasis (proteostasis) is achieved at the level of the cell and organism, and how the threshold of the stress response is set to detect and combat protein misfolding. For metazoans, the requirement for coordinated function and growth imposes additional constraints on the detection, signaling, and response to misfolding, and requires that the HSR is integrated into various aspects of organismal physiology, such as lifespan. This is achieved by hierarchical regulation of heat shock factor 1 (HSF1) by the metabolic state of the cell and centralized neuronal control that could allow optimal resource allocation between cells and tissues. We will examine how protein folding quality control mechanisms in individual cells may be integrated into a multicellular level of control, and further, even custom-designed to support individual variability and impose additional constraints on evolutionary adaptation.

Figure 1.

Cellular protein homeostasis (proteostasis). To maintain proteins in a functionally folded state, cells must find a balance between the intrinsic and extrinsic forces that perturb protein folding and specialized networks of molecular chaperones, folding enzymes, and degradation machinery. Molecular chaperones participate at multiple levels in protein biogenesis: assisting in the de novo folding and protein interactions and preventing deleterious intermolecular interactions.

Figure 2.

Chaperone levels are actively maintained in cells to accommodate the demands of protein folding. All cells and organisms adjust the expression of chaperones and other cytoprotective genes to adapt to changing environmental conditions and ensure recovery following perturbations to proteostasis. At the molecular level, this is mediated by the transcriptional regulation of HS genes by the heat shock factor 1 (HSF1). (A) HSF1 in unstressed metazoan cells is in an inert, monomeric state, transiently bound to chaperones. (B) The current model for the activation of HSF1 and up-regulation of chaperones is that the increased flux of misfolded and damaged proteins that occurs on heat shock or other proteotoxic stressors is met by a corresponding increase in chaperone levels. (C) The attenuation of the HSR following stress is less well understood. It is unclear what happens to the excess chaperone capacity induced in the cell following the resolution of protein misfolding. In fact, exposure of the cell to a mild environmental stress that causes chaperone induction establishes a hormetic state in which cells are protected from a subsequent lethal stress, perhaps because of the excess of chaperones.

Figure 3.

Proteostasis pathways. Multiple interconnected pathways regulate the expression of chaperones and other cytoprotective genes that contribute to maintenance of protein folding homeostasis during growth, development, and aging and under various stress conditions. These complex signaling pathways participate in diverse physiological functions and therefore proteostasis requires precise control over their activities. The cell nonautonomous regulation of the HSR by neurons may allow the integration of stress responses with growth and metabolic state of the animal.

Figure 4.

Proteostasis networks must match the misfolded protein load. (A) Protein misfolding because of genetic variation, including destabilizing polymorphisms, biosynthetic errors such as mistranslation, and various proteotoxic stresses is suppressed by the activity of molecular chaperones and other components of Proteostasis network. (B) Dysfunction of cell-specific proteins, protein complexes, or pathways (target pathway, left edge) because of misfolding may result from excessive competition for limiting components of Proteostasis network (1), from other misfolded species, which can be genetically encoded (competing pathway, right edge), for example in familial variants of conformational disease. Alternatively, competition could be generated by biosynthetic errors, proteotoxic stresses, etc. (2), Dysregulation of Proteostasis network itself by mutations and polymorphisms (3), as well as additional “hits” sustained by the target pathway (4), may all lead to the cell-specific dysfunction of the target pathways. Together, the latter three possibilities may contribute to the development of the sporadic variants of conformational disease.