Protein Kinase A Regulates Molecular Chaperone Transcription and Protein AggregationReportar como inadecuado




Protein Kinase A Regulates Molecular Chaperone Transcription and Protein Aggregation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



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

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados