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Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation

Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impac...

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Autores principales: Wang, Yaqiu, Karki, Rajendra, Mall, Raghvendra, Sharma, Bhesh Raj, Kalathur, Ravi C., Lee, SangJoon, Kancharana, Balabhaskararao, So, Matthew, Combs, Katie L., Kanneganti, Thirumala-Devi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630927/
https://www.ncbi.nlm.nih.gov/pubmed/36198273
http://dx.doi.org/10.1016/j.celrep.2022.111434
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author Wang, Yaqiu
Karki, Rajendra
Mall, Raghvendra
Sharma, Bhesh Raj
Kalathur, Ravi C.
Lee, SangJoon
Kancharana, Balabhaskararao
So, Matthew
Combs, Katie L.
Kanneganti, Thirumala-Devi
author_facet Wang, Yaqiu
Karki, Rajendra
Mall, Raghvendra
Sharma, Bhesh Raj
Kalathur, Ravi C.
Lee, SangJoon
Kancharana, Balabhaskararao
So, Matthew
Combs, Katie L.
Kanneganti, Thirumala-Devi
author_sort Wang, Yaqiu
collection PubMed
description Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impacts of tonic IFN production on health and disease remain enigmatic. Here, we report that caspase-8 negatively regulates type I IFN production by inhibiting the RIPK1-TBK1 axis during homeostasis across multiple cell types and tissues. When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated IFN production, leading to heightened resistance to norovirus infection in macrophages but also early onset lymphadenopathy in mice. Combined deletion of caspase-8 and RIPK1 reduces the type I IFN signaling and lymphadenopathy, highlighting the critical role of RIPK1 in this process. Overall, our study identifies a mechanism to constrain tonic type I IFN during homeostasis which could be targeted for infectious and inflammatory diseases.
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spelling pubmed-96309272022-11-03 Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation Wang, Yaqiu Karki, Rajendra Mall, Raghvendra Sharma, Bhesh Raj Kalathur, Ravi C. Lee, SangJoon Kancharana, Balabhaskararao So, Matthew Combs, Katie L. Kanneganti, Thirumala-Devi Cell Rep Article Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impacts of tonic IFN production on health and disease remain enigmatic. Here, we report that caspase-8 negatively regulates type I IFN production by inhibiting the RIPK1-TBK1 axis during homeostasis across multiple cell types and tissues. When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated IFN production, leading to heightened resistance to norovirus infection in macrophages but also early onset lymphadenopathy in mice. Combined deletion of caspase-8 and RIPK1 reduces the type I IFN signaling and lymphadenopathy, highlighting the critical role of RIPK1 in this process. Overall, our study identifies a mechanism to constrain tonic type I IFN during homeostasis which could be targeted for infectious and inflammatory diseases. 2022-10-04 /pmc/articles/PMC9630927/ /pubmed/36198273 http://dx.doi.org/10.1016/j.celrep.2022.111434 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Wang, Yaqiu
Karki, Rajendra
Mall, Raghvendra
Sharma, Bhesh Raj
Kalathur, Ravi C.
Lee, SangJoon
Kancharana, Balabhaskararao
So, Matthew
Combs, Katie L.
Kanneganti, Thirumala-Devi
Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title_full Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title_fullStr Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title_full_unstemmed Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title_short Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation
title_sort molecular mechanism of ripk1 and caspase-8 in homeostatic type i interferon production and regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630927/
https://www.ncbi.nlm.nih.gov/pubmed/36198273
http://dx.doi.org/10.1016/j.celrep.2022.111434
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