Rotavirus NSP1 activates human NLRP1 inflammasome
- 1Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
- 2The Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
Abstract
While inflammasomes detect and defend against pathogens, the precise mechanisms by which enteric viruses trigger these complexes, and the specific viral components involved remain incompletely understood. In this study, we demonstrate that rotavirus infection robustly induced human NLRP1 inflammasome activation via p38 mitogen-activated protein kinase (MAPK)-dependent and -independent pathways. Utilizing cell lines reconstituted with NLRP1 signaling and reverse genetics-rescued recombinant rotaviruses, we identified non-structural protein 1 (NSP1), a well-characterized viral antagonist of host interferon signaling, as an activator of the NLRP1 inflammasome in the absence of double-stranded RNA. Domain mapping analysis revealed that the C-terminus of NSP1 but not the C-terminal IRF3-binding site was essential for triggering inflammasome activation. Mechanistically, we show that NSP1 induced the proteasomal degradation of NLRP1 to elicit its activation, a process dependent on host neddylation pathways and the Cullin-3/Elongin B/C ubiquitin ligase complex. Together, these findings suggest that RV engages parallel NLRP1 surveillance pathways, including a p38-dependent response to infection, and a novel NSP1-dependent pathway involving the ubiquitin-proteosome system, where a viral strategy aimed at host protein degradation inadvertently trips the human NLRP1 inflammasome wire.
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BibTeX
@misc{zeng2026rotavirus,
title = {{Rotavirus NSP1 activates human NLRP1 inflammasome}},
author = {Qiru Zeng and Jinyi Sun and Stefano Bonazza and Debajyoti Chakraborty and Alexander Borodavka and Siyuan Ding},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761966},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761966v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Rotavirus NSP1 activates human NLRP1 inflammasome
AU - Qiru Zeng
AU - Jinyi Sun
AU - Stefano Bonazza
AU - Debajyoti Chakraborty
AU - Alexander Borodavka
AU - Siyuan Ding
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761966
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761966v1
AB - While inflammasomes detect and defend against pathogens, the precise mechanisms by which enteric viruses trigger these complexes, and the specific viral components involved remain incompletely understood. In this study, we demonstrate that rotavirus infection robustly induced human NLRP1 inflammasome activation via p38 mitogen-activated protein kinase (MAPK)-dependent and -independent pathways. Utilizing cell lines reconstituted with NLRP1 signaling and reverse genetics-rescued recombinant rotaviruses, we identified non-structural protein 1 (NSP1), a well-characterized viral antagonist of host interferon signaling, as an activator of the NLRP1 inflammasome in the absence of double-stranded RNA. Domain mapping analysis revealed that the C-terminus of NSP1 but not the C-terminal IRF3-binding site was essential for triggering inflammasome activation. Mechanistically, we show that NSP1 induced the proteasomal degradation of NLRP1 to elicit its activation, a process dependent on host neddylation pathways and the Cullin-3/Elongin B/C ubiquitin ligase complex. Together, these findings suggest that RV engages parallel NLRP1 surveillance pathways, including a p38-dependent response to infection, and a novel NSP1-dependent pathway involving the ubiquitin-proteosome system, where a viral strategy aimed at host protein degradation inadvertently trips the human NLRP1 inflammasome wire.
SN - 2692-8205
ER -