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.
Highlights
A growing number of human diseases, such as cystic fibrosis, Alzheimer’s disease, and certain types of cancer, are associated with alterations in the protein homeostasis network that lead to protein misfolding, mislocalization, or aggregation [1].renal tubular dysgenesis (RTD) is a severe disorder affecting renal tubular development and is characterized by persistent fetal anuria and perinatal death [2]
Mutations in different components of the renin-angiotensin system have been linked to RTD, and one such class of mutations are those found in the gene that codes for the angiotensinconverting enzyme (ACE) [3]
The correct expression, folding, trafficking and processing of proteins is essential for the overall cellular homeostasis and is emerging as a novel concept known as proteostasis [19]
Summary
A growing number of human diseases, such as cystic fibrosis, Alzheimer’s disease, and certain types of cancer, are associated with alterations in the protein homeostasis network (proteostasis) that lead to protein misfolding, mislocalization, or aggregation [1].RTD is a severe disorder affecting renal tubular development and is characterized by persistent fetal anuria and perinatal death [2]. Mutations in different components of the renin-angiotensin system have been linked to RTD, and one such class of mutations are those found in the gene that codes for the angiotensinconverting enzyme (ACE) [3]. ACE is a zincmetallopeptidase and a key component of the renin-angiotensinaldosterone system involved in the regulation of blood pressure and heart function through the formation of the vasoconstrictor angiotensin II and inactivation of the vasodilator bradykinin [4,5]. The somatic form is abundant in endothelial, epithelial and neuronal cell membranes. Somatic ACE exists as a soluble form that originates from membrane-bound endothelial ACE by the action of a yet unidentified protease. Soluble ACE is found in the plasma, cerebrospinal fluid, seminal liquid, and urine [10,11], and contains two enzymatic domains with a high degree of internal sequence homology [12]. The active sites in the two enzymatic domains display contrasting catalytic and immunological properties and substrate specificities [13,14,15]
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