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Florian Schmidt Lea Jenster
© David Fußhöller / UKB

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P38 as signaling hub for NLRP1 activation in the skin

Ribotoxic stress response to UV-radiation and microbial molecules activate p38, inducing human NLRP1 inflammasome assembly in keratinocytes

Inflammasomes integrate different cues of infection or cellular damage to trigger an inflammatory response. The Nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) expressed in Keratinocytes coordinates inflammation in the skin. A recent study by ImmunoSensation2 scientists the University of Bonn in cooperation with colleagues at the University of Melbourne and the Boston Children’s Hospital has now identified p38 as the key molecule integrating various stress signals and inducing NLRP1 inflammasome assembly in human keratinocytes. The results have been published in the Journal of Experimental Medicine.

As the largest organ of the human body, the skin provides a major barrier to environmental stimuli and pathogens. Painful inflammation can be mounted if this barrier is compromised – as anyone who has ever had a sunburn knows. But how exactly this is triggered was not known in detail until now. "In our study, we took a closer look at the processes involved," explains ImmunoSensation2 member Prof. Dr. Florian Schmidt, who heads a research group at the Institute of Innate Immunity at the University Hospital Bonn. "We have now been able to show that a known cellular stress signaling pathway can trigger these inflammatory responses"

UV stress triggers signal chain

Ultraviolet radiation can cause damage to ribosomal RNAs. This induces the ribotoxic stress response which ultimately leads to the activation of p38 mitogen-activated protein kinases (MAPKs). Also, the radiation induces NLRP1-mediated inflammation. Until now, it was unclear how this exactly happens. Hence, the researchers around Florian Schmidt analyzed the signaling cascades upstream of NLRP1. "Our research shows that p38 molecularly modifies NLRP1, a critical switch for inflammation in the skin, and thus activates it in a novel way. This initiates the assembly of inflammasomes from many molecular building blocks." explains Schmidt, who is also a member of the Transdisciplinary Research Area (TRA) "Life and Health" at the University of Bonn. p38 was shown to directly phosphorylate NLRP1, inducing a subsequent ubiquitination, degradation and nucleation of inflammasomes by the resulting NLRP1 degradation product.

Viruses also activate p38

Interestingly, p38 and NLRP1 are not only activated by UV-radiation. "We were able to show that mosquito-borne viruses can activate NLRP1 through p38 as well," emphasizes Lea-Marie Jenster, a PhD student in the Schmidt lab and the lead author of this study. "These include, for instance, chikungunya virus, which is a major problem in parts of Africa and Asia and could also reach Germany in the wake of climate change." In contrast, activation of NLRP1 by other known mechanisms, as nanobody-mediated ubiquitination, viral proteases, or blocking of the NLRP1 inhibiting dipeptidyl peptidase 9 (DPP9) was found independent of p38 activity.

Taken together, p38 activation is identified as a unifying signaling hub that integrates a variety of cellular stress signals relevant to the skin and thus controls NLRP1 inflammasome activation in karyocytes. "However, not every incoming call for help immediately triggers the assembly of inflammasomes - this only happens when the number and intensity of alerts exceed a certain threshold" Schmidt explains. Sometimes, however, inflammasome formation is controlled not strictly enough - as in the case of sunburn or even some autoimmune diseases. Perhaps p38 opens up a new possibilities to specifically suppress such exuberant immune reactions in the skin in the future.


Participating institutions
In addition to the University Hospital of Bonn and the University of Bonn, the University of Melbourne (Australia) and Boston Children's Hospital (USA) were involved in the study.


Funding

The work was funded by the German Research Foundation (DFG) and the Klaus Tschira Boost Fund.


Publication

Lea-Marie Jenster, Karl-Elmar Lange, Sabine Normann, Anja vom Hemdt, Jennifer D. Wuerth, Lisa D.J. Schiffelers, Yonas M. Tesfamariam, Florian N. Gohr, Laura Klein, Ines H. Kaltheuner, Dorothee J. Lapp, Jacob Mayer, Jonas Moecking, Hidde L. Ploegh, Eicke Latz, Matthias Geyer, Beate M. Kümmerer, Florian I. Schmidt: P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection; Journal of Experimental Medicine; https://doi.org/10.1084/jem.20220837


Contact

Prof. Florian I. Schmidt

Institute of Innate Immunity

University of Bonn

Email: fschmidt@uni-bonn.de

Tel. Office: +49-228/287-51124

Tel. Lab: +49-228/287-54708

mobile: +49-176/70021810

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