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Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; h...

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Autores principales: Gong, Qin, Robinson, Kim, Xu, Chenrui, Huynh, Phuong Thao, Chong, Kelvin Han Chung, Tan, Eddie Yong Jun, Zhang, Jiawen, Boo, Zhao Zhi, Teo, Daniel Eng Thiam, Lay, Kenneth, Zhang, Yaming, Lim, John Soon Yew, Goh, Wah Ing, Wright, Graham, Zhong, Franklin L., Reversade, Bruno, Wu, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794362/
https://www.ncbi.nlm.nih.gov/pubmed/33420028
http://dx.doi.org/10.1038/s41467-020-20319-5
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author Gong, Qin
Robinson, Kim
Xu, Chenrui
Huynh, Phuong Thao
Chong, Kelvin Han Chung
Tan, Eddie Yong Jun
Zhang, Jiawen
Boo, Zhao Zhi
Teo, Daniel Eng Thiam
Lay, Kenneth
Zhang, Yaming
Lim, John Soon Yew
Goh, Wah Ing
Wright, Graham
Zhong, Franklin L.
Reversade, Bruno
Wu, Bin
author_facet Gong, Qin
Robinson, Kim
Xu, Chenrui
Huynh, Phuong Thao
Chong, Kelvin Han Chung
Tan, Eddie Yong Jun
Zhang, Jiawen
Boo, Zhao Zhi
Teo, Daniel Eng Thiam
Lay, Kenneth
Zhang, Yaming
Lim, John Soon Yew
Goh, Wah Ing
Wright, Graham
Zhong, Franklin L.
Reversade, Bruno
Wu, Bin
author_sort Gong, Qin
collection PubMed
description Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIIND(UPA)-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIIND(UPA)-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIIND(UPA). Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIIND(UPA) which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.
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spelling pubmed-77943622021-01-21 Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8 Gong, Qin Robinson, Kim Xu, Chenrui Huynh, Phuong Thao Chong, Kelvin Han Chung Tan, Eddie Yong Jun Zhang, Jiawen Boo, Zhao Zhi Teo, Daniel Eng Thiam Lay, Kenneth Zhang, Yaming Lim, John Soon Yew Goh, Wah Ing Wright, Graham Zhong, Franklin L. Reversade, Bruno Wu, Bin Nat Commun Article Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIIND(UPA)-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIIND(UPA)-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIIND(UPA). Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIIND(UPA) which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes. Nature Publishing Group UK 2021-01-08 /pmc/articles/PMC7794362/ /pubmed/33420028 http://dx.doi.org/10.1038/s41467-020-20319-5 Text en © The Author(s) 2021 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/.
spellingShingle Article
Gong, Qin
Robinson, Kim
Xu, Chenrui
Huynh, Phuong Thao
Chong, Kelvin Han Chung
Tan, Eddie Yong Jun
Zhang, Jiawen
Boo, Zhao Zhi
Teo, Daniel Eng Thiam
Lay, Kenneth
Zhang, Yaming
Lim, John Soon Yew
Goh, Wah Ing
Wright, Graham
Zhong, Franklin L.
Reversade, Bruno
Wu, Bin
Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title_full Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title_fullStr Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title_full_unstemmed Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title_short Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
title_sort structural basis for distinct inflammasome complex assembly by human nlrp1 and card8
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794362/
https://www.ncbi.nlm.nih.gov/pubmed/33420028
http://dx.doi.org/10.1038/s41467-020-20319-5
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