IKKε and TBK1 prevent RIPK1 dependent and independent inflammation
Abstract TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poor...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44372-y |
| _version_ | 1797363050513170432 |
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| author | Remzi Onur Eren Göksu Gökberk Kaya Robin Schwarzer Manolis Pasparakis |
| author_facet | Remzi Onur Eren Göksu Gökberk Kaya Robin Schwarzer Manolis Pasparakis |
| author_sort | Remzi Onur Eren |
| collection | DOAJ |
| description | Abstract TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis. |
| first_indexed | 2024-03-08T16:16:17Z |
| format | Article |
| id | doaj.art-5c238d21d18c457aad9852c3856e63eb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:17Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5c238d21d18c457aad9852c3856e63eb2024-01-07T12:34:44ZengNature PortfolioNature Communications2041-17232024-01-0115111810.1038/s41467-023-44372-yIKKε and TBK1 prevent RIPK1 dependent and independent inflammationRemzi Onur Eren0Göksu Gökberk Kaya1Robin Schwarzer2Manolis Pasparakis3Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneAbstract TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.https://doi.org/10.1038/s41467-023-44372-y |
| spellingShingle | Remzi Onur Eren Göksu Gökberk Kaya Robin Schwarzer Manolis Pasparakis IKKε and TBK1 prevent RIPK1 dependent and independent inflammation Nature Communications |
| title | IKKε and TBK1 prevent RIPK1 dependent and independent inflammation |
| title_full | IKKε and TBK1 prevent RIPK1 dependent and independent inflammation |
| title_fullStr | IKKε and TBK1 prevent RIPK1 dependent and independent inflammation |
| title_full_unstemmed | IKKε and TBK1 prevent RIPK1 dependent and independent inflammation |
| title_short | IKKε and TBK1 prevent RIPK1 dependent and independent inflammation |
| title_sort | ikkε and tbk1 prevent ripk1 dependent and independent inflammation |
| url | https://doi.org/10.1038/s41467-023-44372-y |
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