Cargando…

Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling

Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect...

Descripción completa

Detalles Bibliográficos
Autores principales: Tanzer, Maria C., Bludau, Isabell, Stafford, Che A., Hornung, Veit, Mann, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523534/
https://www.ncbi.nlm.nih.gov/pubmed/34663829
http://dx.doi.org/10.1038/s41467-021-26289-6
_version_ 1784585322153115648
author Tanzer, Maria C.
Bludau, Isabell
Stafford, Che A.
Hornung, Veit
Mann, Matthias
author_facet Tanzer, Maria C.
Bludau, Isabell
Stafford, Che A.
Hornung, Veit
Mann, Matthias
author_sort Tanzer, Maria C.
collection PubMed
description Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Therefore, we combine phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis to identify functional modules of protein phosphorylation. The majority of regulated phosphorylation events can be assigned to an upstream kinase by inhibiting master kinases. Spatial proteomics reveals phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovers a key role for transcriptional cyclin-dependent kinase activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. This resource of TNF-induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/.
format Online
Article
Text
id pubmed-8523534
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-85235342021-11-15 Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling Tanzer, Maria C. Bludau, Isabell Stafford, Che A. Hornung, Veit Mann, Matthias Nat Commun Article Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Therefore, we combine phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis to identify functional modules of protein phosphorylation. The majority of regulated phosphorylation events can be assigned to an upstream kinase by inhibiting master kinases. Spatial proteomics reveals phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovers a key role for transcriptional cyclin-dependent kinase activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. This resource of TNF-induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/. Nature Publishing Group UK 2021-10-18 /pmc/articles/PMC8523534/ /pubmed/34663829 http://dx.doi.org/10.1038/s41467-021-26289-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tanzer, Maria C.
Bludau, Isabell
Stafford, Che A.
Hornung, Veit
Mann, Matthias
Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title_full Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title_fullStr Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title_full_unstemmed Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title_short Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
title_sort phosphoproteome profiling uncovers a key role for cdks in tnf signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523534/
https://www.ncbi.nlm.nih.gov/pubmed/34663829
http://dx.doi.org/10.1038/s41467-021-26289-6
work_keys_str_mv AT tanzermariac phosphoproteomeprofilinguncoversakeyroleforcdksintnfsignaling
AT bludauisabell phosphoproteomeprofilinguncoversakeyroleforcdksintnfsignaling
AT staffordchea phosphoproteomeprofilinguncoversakeyroleforcdksintnfsignaling
AT hornungveit phosphoproteomeprofilinguncoversakeyroleforcdksintnfsignaling
AT mannmatthias phosphoproteomeprofilinguncoversakeyroleforcdksintnfsignaling