title: The caspase-3-p120-RasGAP module generates a NF-κB repressor in response to cellular stress.
abstract: 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.
authors.affiliation: Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Hadi
authors.initials: H
authors.lastname: Khalil
authors.affiliation: Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Loukili
authors.affiliation: Department of Dermatology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Regamey
authors.affiliation: Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cuesta-Marban
authors.affiliation: Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Elettra
authors.initials: E
authors.lastname: Santori
authors.affiliation: Department of Dermatology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Huber
authors.affiliation: Department of Physiology, Biology and Medicine Faculty, University of Lausanne, 1005 Lausanne, Switzerland Christian.Widmann@unil.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments; D051381:Rats; D013312:Stress, Physiological / Q000502:physiology; D020729:p120 GTPase Activating Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D010446:Peptide Fragments; D020729:p120 GTPase Activating Protein; D053148:Caspase 3
keywords: Caspase; Cellular stress; NF-κB; RasGAP