Khalil Hadi, Loukili Noureddine, Regamey Alexandre, Cuesta-Marban Alvaro, Santori Elettra, Huber Marcel, Widmann Christian
Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland.
Department of Dermatology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
J Cell Sci. 2015 Sep 15;128(18):3502-13. doi: 10.1242/jcs.174409. Epub 2015 Jul 29.
The nuclear factor κB (NF-κB) transcription factor is a master regulator of inflammation. Short-term NF-κB activation is generally beneficial. However, sustained NF-κB might be detrimental, directly causing apoptosis of cells or leading to a persistent damaging inflammatory response. NF-κB activity in stressed cells needs therefore to be controlled for homeostasis maintenance. In mildly stressed cells, caspase-3 cleaves p120 RasGAP, also known as RASA1, into an N-terminal fragment, which we call fragment N. We show here that this fragment is a potent NF-κB inhibitor. Fragment N decreases the transcriptional activity of NF-κB by promoting its export from the nucleus. Cells unable to generate fragment N displayed increased NF-κB activation upon stress. Knock-in mice expressing an uncleavable p120 RasGAP mutant showed exaggerated NF-κB activation when their epidermis was treated with anthralin, a drug used for the treatment of psoriasis. Our study provides biochemical and genetic evidence of the importance of the caspase-3-p120-RasGAP stress-sensing module in the control of stress-induced NF-κB activation.
