The Heat Shock Response: Systems Biology of Proteotoxic Stress in Aging and Disease

Morimoto, Richard I.

doi:10.1101/sqb.2012.76.010637

Cited by 357 publications

(319 citation statements)

References 94 publications

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“…Each subgroup comprises several family members and cofactors with distinct and/or overlapping functions, which are localized in various cellular com partments 30,31 . Members can be constitutively expressed or are induced by many different intrinsic or extrin sic stressors 30,[32][33][34] . HSPs that chaperone de novo pro tein folding and refolding include HSP60, HSP70, and HSP90.…”

Section: The Proteostasis Network Componentsmentioning

confidence: 99%

“…Ac, acetyl group; ATF, activating transcription factor; eIF2α, eukaryotic translation initiation factor 2α; HSPA5, heat-shock protein A5 (also known as 75 kDa glucose-regulated protein); IRE1, serine/threonine-protein kinase/endoribonuclease IRE1; PERK, eukaryotic translation initiation factor 2α-kinase 3; XBP1, X-box-binding protein 1. lifespan. Conversely, knockdown of the master switch of the heat shock response, HSF1, reduces lifespan and sensi tizes proteins to misfolding and aggregation 25,32 . Moreover, overexpression of mitochondrial chaperones HSP70 (HSPA9) 138 Disturbed proteostasis and heart function Cardiac remodelling Derailed proteostasis constitutes a major trigger for dys function of cardiomyocytes, but the ensuing changes in overall cardiac performance involve additional path ways, particularly those involved in cardiac remodel ling.…”

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

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Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: The Proteostasis Network Componentsmentioning

confidence: 99%

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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show abstract

“…In comparison with fibroblasts that have undergone fewer passages, senescent fibroblasts exhibit a reduction in the levels of all three proteasome activities and proteasome subunit levels 40 . Several stress responses such as the heat stress response (HSR) induce the expression of chaperones to correct defects in protein folding [7][8][9] . The HSR declines with age contributing to the accumulation of damaged proteins that may overwhelm the proteolytic machinery [7][8][9] .…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

“…Several stress responses such as the heat stress response (HSR) induce the expression of chaperones to correct defects in protein folding [7][8][9] . The HSR declines with age contributing to the accumulation of damaged proteins that may overwhelm the proteolytic machinery [7][8][9] . In addition, the HSR regulates the expression of specific chaperones, such as HSP70, that bind to unfolded proteins to stimulate their degradation by the proteasome.…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

The role of protein clearance mechanisms in organismal ageing and age-related diseases

2014

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“…The versatility of the folding program should, in principle, be able to address challenges such as occurs in AATD-inherited disease through reprogramming [ 18 ]. While HSR [ 3 ] is the universal response found to manage folding in all phyla, in eukaryotes the UPR [ 4 ] has evolved to handle misfolded proteins traversing endomembrane compartments. As such, each compartment relies on multiple but often unknown inputs to elicit highly variable and dynamic responses to handle folding challenges that either address the problem or found to be insurmountable and drive the cell down death pathways.…”

Section: Proactive Proteostatic Signaling Pathways Activated By Z-aatmentioning

confidence: 99%

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

Wang

Balch

2016

Alpha-1 Antitrypsin

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The Heat Shock Response: Systems Biology of Proteotoxic Stress in Aging and Disease

Cited by 357 publications

References 94 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

The role of protein clearance mechanisms in organismal ageing and age-related diseases

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

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