Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells.
Fernando Aprile-GarciaParul TomarBarbara HummelAshkan KhavaranRitwick SawarkarPublished in: Nature structural & molecular biology (2019)
Proteotoxic stress such as heat shock causes heat-shock factor (HSF)-dependent transcriptional upregulation of chaperones. Heat shock also leads to a rapid and reversible downregulation of many genes, a process we term stress-induced transcriptional attenuation (SITA). The mechanism underlying this conserved phenomenon is unknown. Here we report that enhanced recruitment of negative transcription elongation factors to gene promoters in human cell lines induces SITA. A chemical inhibitor screen showed that active translation and protein ubiquitination are required for the response. We further find that proteins translated during heat shock are subjected to ubiquitination and that p38 kinase signaling connects cytosolic translation with gene downregulation. Notably, brain samples of subjects with Huntington's disease also show transcriptional attenuation, which is recapitulated in cellular models of protein aggregation similar to heat shock. Thus our work identifies an HSF-independent mechanism that links nascent-protein ubiquitination to transcriptional downregulation during heat shock, with potential ramifications in neurodegenerative diseases.
Keyphrases
- heat shock
- heat stress
- heat shock protein
- genome wide
- stress induced
- cell proliferation
- signaling pathway
- oxidative stress
- protein protein
- transcription factor
- genome wide identification
- copy number
- amino acid
- binding protein
- gene expression
- preterm infants
- dna methylation
- risk assessment
- multiple sclerosis
- brain injury
- poor prognosis
- drug induced
- resting state
- functional connectivity
- small molecule
- white matter
- blood brain barrier