PT  - JOURNAL ARTICLE
AU  - Lea-Marie Jenster
AU  - Karl-Elmar Lange
AU  - Sabine Normann
AU  - Anja vom Hemdt
AU  - Jennifer D. Wuerth
AU  - Lisa D.J. Schiffelers
AU  - Yonas M. Tesfamariam
AU  - Florian N. Gohr
AU  - Laura Klein
AU  - Ines H. Kaltheuner
AU  - Dorothee J. Lapp
AU  - Jacob Mayer
AU  - Jonas Moecking
AU  - Hidde L. Ploegh
AU  - Eicke Latz
AU  - Matthias Geyer
AU  - Beate M. Kümmerer
AU  - Florian I. Schmidt
TI  - P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection
AID  - 10.1101/2022.01.24.477423
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.24.477423
4099  - http://biorxiv.org/content/early/2022/01/25/2022.01.24.477423.short
4100  - http://biorxiv.org/content/early/2022/01/25/2022.01.24.477423.full
AB  - Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAKα to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAKα, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.Competing Interest StatementEL and FIS are cofounders and shareholders of Dioscure Therapeutics SE and Odyssey Therapeutics; MG and EL are a cofounder and shareholder of IFM Therapeutics; FIS is a consultant and shareholder to IFM Therapeutics. The other authors declare no competing interest.