title: TRIM72 modulates caveolar endocytosis in repair of lung cells.
abstract: Alveolar epithelial and endothelial cell injury is a major feature of the acute respiratory distress syndrome, in particular when in conjunction with ventilation therapies. Previously we showed [Kim SC, Kellett T, Wang S, Nishi M, Nagre N, Zhou B, Flodby P, Shilo K, Ghadiali SN, Takeshima H, Hubmayr RD, Zhao X. Am J Physiol Lung Cell Mol Physiol 307: L449-L459, 2014.] that tripartite motif protein 72 (TRIM72) is essential for amending alveolar epithelial cell injury. Here, we posit that TRIM72 improves cellular integrity through its interaction with caveolin 1 (Cav1). Our data show that, in primary type I alveolar epithelial cells, lack of TRIM72 led to significant reduction of Cav1 at the plasma membrane, accompanied by marked attenuation of caveolar endocytosis. Meanwhile, lentivirus-mediated overexpression of TRIM72 selectively increases caveolar endocytosis in rat lung epithelial cells, suggesting a functional association between these two. Further coimmunoprecipitation assays show that deletion of either functional domain of TRIM72, i.e., RING, B-box, coiled-coil, or PRY-SPRY, abolishes the physical interaction between TRIM72 and Cav1, suggesting that all theoretical domains of TRIM72 are required to forge a strong interaction between these two molecules. Moreover, in vivo studies showed that injurious ventilation-induced lung cell death was significantly increased in knockout (KO) TRIM72(KO) and Cav1(KO) lungs compared with wild-type controls and was particularly pronounced in double KO mutants. Apoptosis was accompanied by accentuation of gross lung injury manifestations in the TRIM72(KO) and Cav1(KO) mice. Our data show that TRIM72 directly and indirectly modulates caveolar endocytosis, an essential process involved in repair of lung epithelial cells through removal of plasma membrane wounds. Given TRIM72's role in endomembrane trafficking and cell repair, we consider this molecule an attractive therapeutic target for patients with injured lungs.
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia; Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio;
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Nagre
authors.affiliation: Thoracic Diseases Research Unit, Mayo Clinic, Rochester, Minnesota;
authors.forename: Shaohua
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio;
authors.forename: Thomas
authors.initials: T
authors.lastname: Kellett
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio;
authors.forename: Ragu
authors.initials: R
authors.lastname: Kanagasabai
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, College of Medicine, The Ohio State University, Columbus, Ohio;
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nishi
authors.affiliation: Division of Pulmonary Pathology, Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.affiliation: Thoracic Diseases Research Unit, Mayo Clinic, Rochester, Minnesota;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Oeckler
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio;
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yalowich
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, College of Medicine, The Ohio State University, Columbus, Ohio;
authors.forename: John
authors.initials: J
authors.lastname: Christman
authors.affiliation: Thoracic Diseases Research Unit, Mayo Clinic, Rochester, Minnesota;
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Hubmayr
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia; Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, College of Medicine, The Ohio State University, Columbus, Ohio; zhaox@evms.edu.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice
chemical_list: D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins
keywords: acute respiratory distress syndrome; alveolar epithelial cells; apoptosis; caveolar endocytosis; lung injury; tripartite motif protein 72