title: SVIP regulates Z variant alpha-1 antitrypsin retro-translocation by inhibiting ubiquitin ligase gp78.
abstract: Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein) interaction with p97/VCP in ZAAT-expressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01). Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Nazli
authors.initials: N
authors.lastname: Khodayari
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Rejean Liqun
authors.initials: RL
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: George
authors.initials: G
authors.lastname: Marek
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Karina
authors.initials: K
authors.lastname: Krotova
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Mariana
authors.initials: M
authors.lastname: Kirst
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers University, New Brunswick, New Jersey, United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Farshid
authors.initials: F
authors.lastname: Rouhani
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Brantly
mesh_terms: D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009154:Mutation; D028044:Phosphate-Binding Proteins; D021381:Protein Transport; D060888:Real-Time Polymerase Chain Reaction; D060285:Receptors, Autocrine Motility Factor / Q000037:antagonists & inhibitors*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D028044:Phosphate-Binding Proteins; C569017:SVIP protein, human; D000515:alpha 1-Antitrypsin; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor