Degradation mechanism of a Golgi-retained distal tubular acidosis mutant of the kidney Anion Exchanger 1 in renal cells

• Author / Creator

  Berrini, Mattia

• Distal renal tubular acidosis (dRTA) is a renal disease caused in some cases by
  mutations in the SLC4A1 gene encoding the kidney anion exchanger 1 (kAE1).
  Both recessive and dominant mutations result in mis-trafficking of proteins,
  preventing them from reaching the basolateral membrane of renal epithelial cells
  where their function is needed. kAE1 G701D is a functional, Golgi-retained
  dRTA mutant. The purpose of this thesis is to understand the degradation
  pathways of kAE1 G701D. We show that this mutant is poly-ubiquitylated and
  degraded by both lysosomal and proteasomal pathways. We provide evidence that
  the Nedd4 family interacting protein 1 (Ndfip1) interacts with kAE1 G701D,
  suggesting a possible role of Ndfip1 in the ubiquitylation process of this mutant.
  Also, we show that this mutant reaches temporarily the cell surface where it is
  endocytosed and degraded by the lysosomes via a peripheral quality-control
  machinery dependent mechanism. Furthermore we show that the function of
  kAE1 G701D is rescued at the cell surface upon inhibition of the lysosome and
  incubation with the chemical chaperone dimethyl sulfoxide (DMSO).
  This study suggests that modulating the peripheral quality-control
  machinery may provide novel therapeutic strategies for the treatment of dRTA
  patients.

• Subjects / Keywords

  • Kidney anion exchanger 1
  • Golgi-retained dRTA mutant
  • Peripheral quality-control machinery
  • Distal renal tubular acidosis

• Graduation date

  Fall 2014

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3V67B

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.