title: Impaired proteostasis contributes to renal tubular dysgenesis.
abstract: Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Rita Machado
authors.initials: RM
authors.lastname: de Oliveira
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Marijanovic
authors.forename: Filipe
authors.initials: F
authors.lastname: Carvalho
authors.forename: Gabriel Miltenberger
authors.initials: GM
authors.lastname: Miltényi
authors.forename: Joana Estevão
authors.initials: JE
authors.lastname: Matos
authors.forename: Sandra
authors.initials: S
authors.lastname: Tenreiro
authors.forename: Sónia
authors.initials: S
authors.lastname: Oliveira
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Enguita
authors.forename: Rosário
authors.initials: R
authors.lastname: Stone
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004795:Enzyme Stability; D005260:Female; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007687:Kidney Tubules, Proximal / Q000002:abnormalities / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014564:Urogenital Abnormalities / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy
chemical_list: D007703:Peptidyl-Dipeptidase A