Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis.
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
Author Information
Kim Samirah Robinson: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
Gee Ann Toh: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
Muhammad Jasrie Firdaus: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
Khek Chian Tham: The A*STAR Skin Research Labs , Singapore, Singapore. ORCID
Pritisha Rozario: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
Chrissie K Lim: Institute of Molecular and Cell Biology , Agency for Science, Technology and Research, Singapore, Singapore. ORCID
Ying Xiu Toh: The A*STAR Skin Research Labs , Singapore, Singapore. ORCID
Zhi Heng Lau: The A*STAR Skin Research Labs , Singapore, Singapore. ORCID
Sophie Charlotte Binder: Institute of Innate Immunity, Medical Faculty, University of Bonn , Bonn, Germany. ORCID
Jacob Mayer: Institute of Innate Immunity, Medical Faculty, University of Bonn , Bonn, Germany. ORCID
Carine Bonnard: The A*STAR Skin Research Labs , Singapore, Singapore. ORCID
Florian I Schmidt: Institute of Innate Immunity, Medical Faculty, University of Bonn , Bonn, Germany. ORCID
John E A Common: The A*STAR Skin Research Labs , Singapore, Singapore. ORCID
Franklin L Zhong: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
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.
