Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis

Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis

Journal of Experimental Medicine

10.1084/jem.20230105

http://dx.doi.org/10.1084/jem.20230105

Kim Samirah Robinson, Gee Ann Toh, Muhammad Jasrie Firdaus, Khek Chian Tham, Pritisha Rozario, Chrissie K. Lim, Ying Xiu Toh, Zhi Heng Lau, Sophie Charlotte Binder, Jacob Mayer, Carine Bonnard, Florian I. Schmidt, John E.A. Common, Franklin L. Zhong

Genetics and Molecular Biology

29 August 2023

Robinson, K. S., Toh, G. A., Firdaus, M. J., Tham, K. C., Rozario, P., Lim, C. K., Toh, Y. X., Lau, Z. H., Binder, S. C., Mayer, J., Bonnard, C., Schmidt, F. I., Common, J. E. A., & Zhong, F. L. (2023). Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis. Journal of Experimental Medicine, 220(10). https://doi.org/10.1084/jem.20230105

The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers RSR-dependent inflammasome activation in primary human keratinocytes. This process requires iron-mediated DT production in the bacteria, as well as diphthamide synthesis and ZAKα/p38-driven NLRP1 phosphorylation in host cells. NLRP1 deletion abrogates IL-1β and IL-18 secretion by DT-intoxicated keratinocytes, while ZAKα deletion or inhibition additionally limits both pyroptotic and inflammasome-independent non-pyroptotic cell death. Consequently, pharmacologic inhibition of ZAKα is more effective than caspase-1 inhibition at protecting the epidermal barrier in a 3D skin model of cutaneous diphtheria. In summary, these findings implicate ZAKα-driven RSR and the NLRP1 inflammasome in antibacterial immunity and might explain certain aspects of diphtheria pathogenesis.

Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

This research / project is supported by the National Research Foundation Singapore - NRF Fellowship
Grant Reference no. : NRF-NRFF11-2019-0006

This research / project is supported by the Ministry of Education - Tier 2 grant
Grant Reference no. : T2EP30222-0033

This research / project is supported by the A*STAR - The Singapore Therapeutics Development Review (STDR)
Grant Reference no. : H22G0a0002

This research / project is supported by the BMRC EDB NRF - IAF-PP grants - Skin Research Institute of Singapore
Grant Reference no. : H17/01/a0/ 004

This research / project is supported by the A*STAR- EDB-NRF - IAF-PP grant - ‘Asian Skin Microbiome Program 2.0’
Grant Reference no. : H22J1a0040

This research / project is supported by the A*STAR - Career Development Fund
Grant Reference no. : CDA-C210812053

https://oar.a-star.edu.sg/communities-collections/articles/20077

0022-1007
1540-9538

Skin Research Lab