CFTR SIGNALING MECHANISMS AND THEIR EFFECTS ON MITOCHONDRIA

ANGEL GABRIEL VALDIVIESO; MORI, CONSUELO;; TOMÁS SANTA COLOMA; MASSIP-COPIZ, M.; CLAUZURE, MARIÁNGELES

Mar del Plata

Congreso; LXIII Reunión de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Mutations in the CFTR gene cause cystic fibrosis. Whenthe CFTR chloride channel was cloned most work focusedon non-genomic effects of CFTR. We insteadhypothesized that the complex cystic fibrosis (CF) phenotypeshould be the result of the differential regulationof a net of CFTR-dependent genes. By using differentialdisplay (DD), we demonstrated that many genes showeddifferential expression between CF cells and CF ?corrected?cells. The first CFTR-dependent gene characterizedwas c-Src, which in turn up-modulated MUC1. Then,we focused in two spots that, contrary to c-Src, showedreduced expression on CF cells. Both DD spots correspondedto mitochondrial proteins, MTND4 and CISD1(a new gene), the first associated to a reduced mitochondrialcomplex I (mCx-I) activity in CF cells. We then foundthat IL-1β produced an autocrine positive feed-back loopthat increased its own expression and activity and wasresponsible for the mtCx-I failure and the increased oxidativestress in CF cells. For the second gene, CISD1,codified by the nuclear genome, it has been very difficultto assign a function, and many distinct functions hasbeen attributed by other authors. Then, we hypothesizedthat the signal regulating the differential gene expressionin CF could be the intracellular Cl- concentration. Thus,by using DD, we found the existence of Cl- -dependentgenes, including GRLX5 and RPS27, and showed that Clwasacting as a second-messenger for CFTR. Then, wedemonstrated that increased intracellular Cl- induced IL-1β secretion through a complex mechanism not yet completelyunderstood, which might involve several parallelpathways. In fact, we demonstrated that Cl- modulatesIL-1β expression and secretion through a novel mechanismof NLRP3 inflammasome activation. In conclusion,Cl-behaves as a signaling effector and proinflammatorysignal, regulating the expression of specific genes, someof them involved in modulation of mitochondrial activity.