Protein Kinase A Regulates Molecular Chaperone Transcription and Protein Aggregation

Yue Zhang,Thomas Prince,Stuart K Calderwood,Ayesha Murshid

doi:10.1371/journal.pone.0028950

Yue Zhang, Thomas Prince + Show 2 more

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https://doi.org/10.1371/journal.pone.0028950

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Journal: PloS one	Publication Date: Dec 22, 2011
Citations: 63	License type: CC BY 4.0

Affiliation: Beth Israel Deaconess Medical Center, Harvard University

Abstract

Heat shock factor 1 (HSF1) regulates one of the major pathways of protein quality control and is essential for deterrence of protein-folding disorders, particularly in neuronal cells. However, HSF1 activity declines with age, a change that may open the door to progression of neurodegenerative disorders such as Huntington's disease. We have investigated mechanisms of HSF1 regulation that may become compromised with age. HSF1 binds stably to the catalytic domain of protein kinase A (PKAcα) and becomes phosphorylated on at least one regulatory serine residue (S320). We show here that PKA is essential for effective transcription of HSP genes by HSF1. PKA triggers a cascade involving HSF1 binding to the histone acetylase p300 and positive translation elongation factor 1 (p-TEFb) and phosphorylation of the c-terminal domain of RNA polymerase II, a key mechanism in the downstream steps of HSF1-mediated transcription. This cascade appears to play a key role in protein quality control in neuronal cells expressing aggregation-prone proteins with long poly-glutamine (poly-Q) tracts. Such proteins formed inclusion bodies that could be resolved by HSF1 activation during heat shock. Resolution of the inclusions was inhibited by knockdown of HSF1, PKAcα, or the pTEFb component CDK9, indicating a key role for the HSF1-PKA cascade in protein quality control.

Highlights

Heat shock factor 1 (HSF1) regulates the expression of molecular chaperones and thereby controls one of the most essential arms of the protein quality control network [1,2]
We have shown in a recent study that that HSF1 binds to the catalytic domain of protein kinase A (PKAca) and becomes phosphorylated on a PKA consensus phosphorylation site required for transcriptional activation of downstream gene expression [4]
As heat shock transcription has been shown to be activated by histone deacetylase inhibitors, we examined the possibility that stressinduced, PKA-dependent HSF1 activation may involve interaction with histone acetylases [5,6]

Summary

Introduction

HSF1 regulates the expression of molecular chaperones and thereby controls one of the most essential arms of the protein quality control network [1,2]. Activation of the hsp gene by stress in Drosophila requires HSF association with positive translation elongation factor 1 p-P-TEFb and downstream hyperphosphorylation of the C-terminal domain (CTD) of RNA polymerase II [7]. We demonstrate that PKAca is required for coordinate p300 binding and p-TEFb association with HSF1 on the chromatin of heat shock-induced genes and for stress-induced transcription. This cascade was required for phosphorylation at the 2 position in the repeat sequences of the C-terminal tail of RNA poll II on heat-inducible promoters. We found that activation of HSF1 by protein stress depletes the levels of intracellular protein inclusion bodies containing aggregation– prone, poly-Q containing proteins in neuronal cells an effect abrogated by targeting HSF1, PKAca or the component CDK9 of p-TEFb

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