title: Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis.
abstract: Fus1, encoded by a 3p21.3 tumour suppressor gene, is down-regulated, mutated or lost in the majority of inflammatory thoracic malignancies. The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation. Asbestos treatment resulted in a decreased Fus1 expression in wild-type (WT) peritoneal immune cells, suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response. Untreated Fus1(-/-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice, pointing at ongoing chronic inflammation. Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos, reflected in decreased immune organ weight and peritoneal fluid protein concentration, along with an increased proportion of peritoneal macrophages. Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory, anti-oxidant and genotoxic stress response proteins ERK1/2, NFκB, SOD2, γH2AX, etc. Moreover, Fus1(-/-) mice demonstrated altered dynamics of pro- and anti-inflammatory cytokine expression, such as IFNγ, TNFα, IL-1A, IL-1B and IL-10. 'Late' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states. We observed an asbestos-related difference in the size of CD3(+) CD4(-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice. Finally, we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters (ROS production, mitochondrial potential and UCP2 expression) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells, thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Uzhachenko
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ivanov
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Alla V
authors.initials: AV
authors.lastname: Ivanova
mesh_terms: D000818:Animals; D001194:Asbestos / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D023421:Models, Animal; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: D016207:Cytokines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D001194:Asbestos