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Human NLRP1 is activated by ZAKɑ-driven ribotoxic stress response

Kim S. Robinson, Gee Ann Toh, Pritisha Rozario, Shima Bayat, Zijin Sun, Stefan Bauernfried, Rhea Nadkarni, Cassandra R. Harapas, Chrissie K. Lim, Werncui Chu, Kiat Yi Tan, Carine Bonnard, Radoslaw Sobota, John E. Connolly, Seth L. Masters, Kaiwen W. Chen, Lena Ho, Veit Hornung, Franklin L. Zhong
doi: https://doi.org/10.1101/2022.01.24.477516
Kim S. Robinson
1Skin Research Institute of Singapore (SRIS), #17-01 Clinical Sciences Building, 11 Mandalay Road, 308232, Singapore
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Gee Ann Toh
2Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore
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Pritisha Rozario
2Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore
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Shima Bayat
2Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore
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Zijin Sun
2Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore
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Stefan Bauernfried
6Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
7Max-Planck Institute of Biochemistry, Martinsried, Germany
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Rhea Nadkarni
3Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore
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Cassandra R. Harapas
4Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
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Chrissie K. Lim
8Institute of Molecular and Cell Biology, A*STAR, Singapore
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Werncui Chu
3Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore
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Kiat Yi Tan
9Immunology Translational Research Programme and Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Carine Bonnard
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Radoslaw Sobota
8Institute of Molecular and Cell Biology, A*STAR, Singapore
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John E. Connolly
9Immunology Translational Research Programme and Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Seth L. Masters
4Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
5Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia
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Kaiwen W. Chen
9Immunology Translational Research Programme and Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Lena Ho
3Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore
8Institute of Molecular and Cell Biology, A*STAR, Singapore
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Veit Hornung
6Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
7Max-Planck Institute of Biochemistry, Martinsried, Germany
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Franklin L. Zhong
1Skin Research Institute of Singapore (SRIS), #17-01 Clinical Sciences Building, 11 Mandalay Road, 308232, Singapore
2Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore
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  • For correspondence: franklin.zhong@ntu.edu.sg
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ABSTRACT

Human NLRP1 is a multifunctional inflammasome sensor predominantly expressed in skin and airway epithelium; however its function in skin-specific immunity and its mechanisms of activation are not fully understood. Here we report that human NLRP1 is specifically activated by the ZAKɑ- driven ribotoxic stress response pathway (RSR) induced by ultraviolet B (UVB) irradiation or select microbial ribotoxins. Biochemically, RSR-triggered NLRP1 activation requires ZAKɑ- dependent hyperphosphorylation of a human-specific linker region of NLRP1 (NLRP1DR), leading to the ‘functional degradation’ of the auto-inhibitory NLRP1 N-terminal fragment. Additionally, we show that fusing NLRP1DR to the signaling domains of CARD8, which in itself is insensitive to RSR, creates a minimal inflammasome sensor for UVB and ribotoxins. In summary, these discoveries resolve the mechanisms of UVB sensing by human NLRP1, identify ZAKɑ-activating toxins as novel human NLRP1 activators, and establish NLRP1 inflammasome-dependent pyroptosis as an integral component of the ribotoxic stress response in primary human cells.

  1. UVB-induced NLRP1 activation in human keratinocytes involves a nuclear DNA-independent stress response involving photodamaged RNA

  2. ZAKɑ kinase is required for UVB-triggered, but not VbP- or dsRNA-induced human NLRP1 activation

  3. ZAKɑ-activating microbial ribotoxins specifically activate the NLRP1 inflammasome in multiple primary human cell types

  4. Hyperphosphorylation of a linker region (NLRP1DR) is required for RSR-dependent human NLRP1 activation

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 25, 2022.
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Human NLRP1 is activated by ZAKɑ-driven ribotoxic stress response
Kim S. Robinson, Gee Ann Toh, Pritisha Rozario, Shima Bayat, Zijin Sun, Stefan Bauernfried, Rhea Nadkarni, Cassandra R. Harapas, Chrissie K. Lim, Werncui Chu, Kiat Yi Tan, Carine Bonnard, Radoslaw Sobota, John E. Connolly, Seth L. Masters, Kaiwen W. Chen, Lena Ho, Veit Hornung, Franklin L. Zhong
bioRxiv 2022.01.24.477516; doi: https://doi.org/10.1101/2022.01.24.477516
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Human NLRP1 is activated by ZAKɑ-driven ribotoxic stress response
Kim S. Robinson, Gee Ann Toh, Pritisha Rozario, Shima Bayat, Zijin Sun, Stefan Bauernfried, Rhea Nadkarni, Cassandra R. Harapas, Chrissie K. Lim, Werncui Chu, Kiat Yi Tan, Carine Bonnard, Radoslaw Sobota, John E. Connolly, Seth L. Masters, Kaiwen W. Chen, Lena Ho, Veit Hornung, Franklin L. Zhong
bioRxiv 2022.01.24.477516; doi: https://doi.org/10.1101/2022.01.24.477516

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