Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions.
Animals
Cyclin-Dependent Kinase 8
/ genetics
Cyclin-Dependent Kinases
/ genetics
Fibroblasts
/ drug effects
HCT116 Cells
Host-Pathogen Interactions
Humans
Interferon-gamma
/ pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
RNA Polymerase II
/ metabolism
STAT1 Transcription Factor
/ metabolism
Signal Transduction
Transcription, Genetic
/ drug effects
Vesiculovirus
/ pathogenicity
CDK19
CDK8
Mediator kinase
RNA polymerase II
STAT1
cortistatin A
eRNA
interferon
promoter-proximal pausing
transcription
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
07 11 2019
07 11 2019
Historique:
received:
16
05
2019
revised:
03
07
2019
accepted:
25
07
2019
pubmed:
10
9
2019
medline:
26
2
2020
entrez:
10
9
2019
Statut:
ppublish
Résumé
Transcriptional responses to external stimuli remain poorly understood. Using global nuclear run-on followed by sequencing (GRO-seq) and precision nuclear run-on sequencing (PRO-seq), we show that CDK8 kinase activity promotes RNA polymerase II pause release in response to interferon-γ (IFN-γ), a universal cytokine involved in immunity and tumor surveillance. The Mediator kinase module contains CDK8 or CDK19, which are presumed to be functionally redundant. We implemented cortistatin A, chemical genetics, transcriptomics, and other methods to decouple their function while assessing enzymatic versus structural roles. Unexpectedly, CDK8 and CDK19 regulated different gene sets via distinct mechanisms. CDK8-dependent regulation required its kinase activity, whereas CDK19 governed IFN-γ responses through its scaffolding function (i.e., it was kinase independent). Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription factor (TF) during IFN-γ stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pathway TFs. Cytokines such as IFN-γ rapidly mobilize TFs to "reprogram" cellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional reprogramming.
Identifiants
pubmed: 31495563
pii: S1097-2765(19)30589-1
doi: 10.1016/j.molcel.2019.07.034
pmc: PMC6842433
mid: NIHMS1536540
pii:
doi:
Substances chimiques
IFNG protein, human
0
IFNG protein, mouse
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
Stat1 protein, mouse
0
Interferon-gamma
82115-62-6
CDK19 protein, human
EC 2.7.11.22
CDK19 protein, mouse
EC 2.7.11.22
CDK8 protein, human
EC 2.7.11.22
Cdk8 protein, mouse
EC 2.7.11.22
Cyclin-Dependent Kinase 8
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
485-499.e8Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM117370
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008759
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150305
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA117907
Pays : United States
Organisme : Austrian Science Fund FWF
ID : P 31848
Pays : Austria
Organisme : NIGMS NIH HHS
ID : T32 GM142607
Pays : United States
Organisme : NIH HHS
ID : S10 OD012300
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM120109
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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