title: Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr ΔF508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery.
abstract: Cystic fibrosis is the most common inherited lethal disease in Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), of which the cftr ΔF508 mutation is the most common. ΔF508 macrophages are intrinsically defective in autophagy because of the sequestration of essential autophagy molecules within unprocessed CFTR aggregates. Defective autophagy allows Burkholderia cenocepacia (B. cepacia) to survive and replicate in ΔF508 macrophages. Infection by B. cepacia poses a great risk to cystic fibrosis patients because it causes accelerated lung inflammation and, in some cases, a lethal necrotizing pneumonia. Autophagy is a cell survival mechanism whereby an autophagosome engulfs non-functional organelles and delivers them to the lysosome for degradation. The ubiquitin binding adaptor protein SQSTM1/p62 is required for the delivery of several ubiquitinated cargos to the autophagosome. In WT macrophages, p62 depletion and overexpression lead to increased and decreased bacterial intracellular survival, respectively. In contrast, depletion of p62 in ΔF508 macrophages results in decreased bacterial survival, whereas overexpression of p62 leads to increased B. cepacia intracellular growth. Interestingly, the depletion of p62 from ΔF508 macrophages results in the release of the autophagy molecule beclin1 (BECN1) from the mutant CFTR aggregates and allows its redistribution and recruitment to the B. cepacia vacuole, mediating the acquisition of the autophagy marker LC3 and bacterial clearance via autophagy. These data demonstrate that p62 differentially dictates the fate of B. cepacia infection in WT and ΔF508 macrophages.
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Basant A
authors.initials: BA
authors.lastname: Abdulrahman
authors.forename: Arwa Abu
authors.initials: AA
authors.lastname: Khweek
authors.forename: Anwari
authors.initials: A
authors.lastname: Akhter
authors.forename: Kyle
authors.initials: K
authors.lastname: Caution
authors.forename: Mia
authors.initials: M
authors.lastname: Tazi
authors.forename: Hoda
authors.initials: H
authors.lastname: Hassan
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Rowland
authors.forename: Sankalp
authors.initials: S
authors.lastname: Malhotra
authors.forename: Famke
authors.initials: F
authors.lastname: Aeffner
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valvano
authors.forename: Amal O
authors.initials: AO
authors.lastname: Amer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D019121:Burkholderia Infections / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D057508:Burkholderia cenocepacia / Q000502:physiology; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050296:Microbial Viability; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D000071456:Sequestosome-1 Protein; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator