Protein Kinase A Regulates Molecular Chaperone Transcription and Protein AggregationReport as inadecuate




Protein Kinase A Regulates Molecular Chaperone Transcription and Protein Aggregation - Download this document for free, or read online. Document in PDF available to download.

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 PKAcĪ± 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, PKAcĪ±, or the pTEFb component CDK9, indicating a key role for the HSF1-PKA cascade in protein quality control.



Author: Yue Zhang , Ayesha Murshid , Thomas Prince, Stuart K. Calderwood

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents