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...
Autores principales: | , , , , |
---|---|
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 |