The CoV-Y domain of SARS-CoV-2 Nsp3 interacts with BRAP to stimulate NF-κB signaling and induce host inflammatory responses
Wang, Kai ; Ni, Xincheng ; Deng, Xinyue ; Nan, Jie LU
; Ma-Lauer, Yue
; von Brunn, Albrecht
; Zeng, Rui
and Lei, Jian
(2024)
In International Journal of Biological Macromolecules
280.
- Abstract
Non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome. It consists of multiple domains that perform critical functions during the viral life cycle. CoV-Y is the most C-terminal domain of Nsp3, and it exhibits evolutionary conservation across diverse CoVs; however, the exact biological function of CoV-Y remains unclear. Here, we determined the crystal structure of CoV-Y of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp3 using the single-wavelength anomalous diffraction method. We revealed the interaction between CoV-Y and the host BRCA1-associated protein (BRAP) using immunoprecipitation-mass spectrometry experiments. This interaction was subsequently confirmed in cellular... (More)
Non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome. It consists of multiple domains that perform critical functions during the viral life cycle. CoV-Y is the most C-terminal domain of Nsp3, and it exhibits evolutionary conservation across diverse CoVs; however, the exact biological function of CoV-Y remains unclear. Here, we determined the crystal structure of CoV-Y of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp3 using the single-wavelength anomalous diffraction method. We revealed the interaction between CoV-Y and the host BRCA1-associated protein (BRAP) using immunoprecipitation-mass spectrometry experiments. This interaction was subsequently confirmed in cellular assays, and the precise binding-regions between these two proteins were clarified. We found that this interaction is conserved in SARS-CoV and Middle East respiratory syndrome coronavirus. Next, we demonstrated that CoV-Y enhances IκBα and IκBβ phosphorylation and promotes the nuclear translocation of the downstream NF-κB members p50 and p65 through binding to BRAP. The CoV-Y–BRAP interaction can upregulate the transcript levels of the host inflammatory cytokines. Overall, our findings illustrate the biological function of CoV-Y for the first time and provide novel insights into coronavirus regulation of host inflammatory responses, as well as a possible target for antiviral drug development.
(Less)
- author
- Wang, Kai
; Ni, Xincheng
; Deng, Xinyue
; Nan, Jie
LU
; Ma-Lauer, Yue
; von Brunn, Albrecht
; Zeng, Rui
and Lei, Jian
- organization
- publishing date
- 2024-11
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Coronavirus, Host protein, NF-κB pathway, Non-structural protein, Protein–protein interaction
- in
- International Journal of Biological Macromolecules
- volume
- 280
- article number
- 136123
- publisher
- Elsevier
- external identifiers
-
- scopus:85205345003
- pmid:39343285
- ISSN
- 0141-8130
- DOI
- 10.1016/j.ijbiomac.2024.136123
- language
- English
- LU publication?
- yes
- id
- 2ecc8334-5c8e-4034-9716-13029645293f
- date added to LUP
- 2024-11-27 13:36:43
- date last changed
- 2025-07-10 08:22:47
@article{2ecc8334-5c8e-4034-9716-13029645293f,
abstract = {{<p>Non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome. It consists of multiple domains that perform critical functions during the viral life cycle. CoV-Y is the most C-terminal domain of Nsp3, and it exhibits evolutionary conservation across diverse CoVs; however, the exact biological function of CoV-Y remains unclear. Here, we determined the crystal structure of CoV-Y of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp3 using the single-wavelength anomalous diffraction method. We revealed the interaction between CoV-Y and the host BRCA1-associated protein (BRAP) using immunoprecipitation-mass spectrometry experiments. This interaction was subsequently confirmed in cellular assays, and the precise binding-regions between these two proteins were clarified. We found that this interaction is conserved in SARS-CoV and Middle East respiratory syndrome coronavirus. Next, we demonstrated that CoV-Y enhances IκBα and IκBβ phosphorylation and promotes the nuclear translocation of the downstream NF-κB members p50 and p65 through binding to BRAP. The CoV-Y–BRAP interaction can upregulate the transcript levels of the host inflammatory cytokines. Overall, our findings illustrate the biological function of CoV-Y for the first time and provide novel insights into coronavirus regulation of host inflammatory responses, as well as a possible target for antiviral drug development.</p>}},
author = {{Wang, Kai and Ni, Xincheng and Deng, Xinyue and Nan, Jie and Ma-Lauer, Yue and von Brunn, Albrecht and Zeng, Rui and Lei, Jian}},
issn = {{0141-8130}},
keywords = {{Coronavirus; Host protein; NF-κB pathway; Non-structural protein; Protein–protein interaction}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{International Journal of Biological Macromolecules}},
title = {{The CoV-Y domain of SARS-CoV-2 Nsp3 interacts with BRAP to stimulate NF-κB signaling and induce host inflammatory responses}},
url = {{http://dx.doi.org/10.1016/j.ijbiomac.2024.136123}},
doi = {{10.1016/j.ijbiomac.2024.136123}},
volume = {{280}},
year = {{2024}},
}