Abstract
Author SummaryThe function of all proteins is dependent on achieving the correct folded state, a process referred to as protein homeostasis or proteostasis. Cellular proteostasis is maintained by diverse signaling pathways, including the heat shock response (HSR), which protects proteins in the face of acute stress. However, genetic disorders are a challenge to cells, since the mutated protein will often fail to fold properly and function correctly. We have discovered that the chronic expression of such disease-causing proteins can trigger the sustained activation of the HSR in a failed attempt to correct the associated misfolding defect. Such chronic HSR activation presents an unanticipated challenge to the cell by initiating a sustained state of stress management, which leads to a general protein-folding deficiency. This in turn further exacerbates the disease phenotype—a condition we have termed maladaptive. We show that down-regulation of this maladaptive stress response (MSR) restores cellular protein folding and improves the disease condition in loss-of-function disorders such as cystic fibrosis, Niemann-Pick disease and alpha-1-antitrypsin deficiency, as well as gain-of-toxic-function diseases such as Alzheimer's disease. MSR management therefore potentially represents an important therapeutic first step in regulating the progression of human disease associated with chronic protein misfolding.
Highlights
The transition from protein folding to misfolding, in both normal physiology and disease, is dynamically managed by multiple proteostatic pathways [1,2]
We observed that in the absence of heat shock (HS), F508del-expressing cells already exhibited increased heat shock transcription factor 1 (HSF1)-P relative to that seen in WT-expressing cells (Figure 1A, 1D), revealing that the heat shock response (HSR) pathway was already hyperactive in these cells
We observed a significant increase in mRNA levels of the HSF1-responsive genes, HspA1A (I-Hsp70), Hsp90a (I-Hsp90), and DNAJB1 (I-Hsp40), relative to that seen in WT-expressing and in isogenic cells lacking cystic fibrosis transmembrane conductance regulator (CFTR) (CFTR 2/2) (Figure 1G)
Summary
The transition from protein folding to misfolding, in both normal physiology and disease, is dynamically managed by multiple proteostatic pathways [1,2]. Qstate managers of each protein fold draw from the proteostasis pool of molecular chaperones (Hsp40s, Hsc70s, Hsp70s, and Hsp90), small heat shock proteins, and ubiquitin-based degradation components [3,5,12,13,14] These managers are responsive to Author Summary. We have discovered that the chronic expression of such disease-causing proteins can trigger the sustained activation of the HSR in a failed attempt to correct the associated misfolding defect Such chronic HSR activation presents an unanticipated challenge to the cell by initiating a sustained state of stress management, which leads to a general protein-folding deficiency. This in turn further exacerbates the disease phenotype—a condition we have termed maladaptive. MSR management potentially represents an important therapeutic first step in regulating the progression of human disease associated with chronic protein misfolding
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