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PMID: 21536706 Published · epublish English Journal Article Research Support, N.I.H., Extramural Review

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

Cold Spring Harbor perspectives in biology ·Vol. 3 ·No. 6 ·2011-06-01

Gidalevitz T, Prahlad V, Morimoto RI

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.

MeSH Terms
Animals Genetic Variation Heat-Shock Proteins/metabolism Heat-Shock Response Homeostasis Humans Molecular Chaperones/metabolism,physiology Protein Folding Proteome Signal Transduction
Chemicals
Heat-Shock Proteins Molecular Chaperones Proteome
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gidalevitz Tali
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
Prahlad Veena
Morimoto Richard I
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Article Info
Journal
Cold Spring Harbor perspectives in biology
Abbr.
Cold Spring Harb Perspect Biol
ISSN
1943-0264
DOI
10.1101/cshperspect.a009704
Published
2011-06-01
Epub
2011-00-01
Language
English
Region
United States
NLM ID
101513680
PMCID
PMC3098679
Subset
IM
Grants
NINDS NIH HHS · R01 NS047331 · United States
NIGMS NIH HHS · R37 GM038109 · United States
NIA NIH HHS · R37 AG026647 · United States
NINDS NIH HHS · NS047331 · United States
NIGMS NIH HHS · R01 GM038109 · United States
NIGMS NIH HHS · GM081192 · United States
NIA NIH HHS · AG026647 · United States
NIA NIH HHS · R01 AG026647 · United States
NIGMS NIH HHS · GM038109 · United States
External Links
PubMed source DOI: 10.1101/cshperspect.a009704 PMC Full Text View journal details
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