Abstract
BackgroundProtein-tyrosine sulfation is a post-translational modification of an unknown number of secreted and membrane proteins mediated by two known Golgi tyrosylprotein sulfotransferases (TPST-1 and TPST-2). We reported that Tpst2-/- mice have mild-moderate primary hypothyroidism, whereas Tpst1-/- mice are euthyroid. While using magnetic resonance imaging (MRI) to look at the thyroid gland we noticed that the salivary glands in Tpst2-/- mice appeared smaller than in wild type mice. This prompted a detailed analysis to compare salivary gland structure and function in wild type, Tpst1-/-, and Tpst2 -/- mice.Methodology/Principal FindingsQuantitative MRI imaging documented that salivary glands in Tpst2-/- females were ≈ 30% smaller than wild type or Tpst1-/- mice and that the granular convoluted tubules in Tpst2-/- submandibular glands were less prominent and were almost completely devoid of exocrine secretory granules compared to glands from wild type or Tpst1-/- mice. In addition, pilocarpine–induced salivary flow and salivary α-amylase activity in Tpst2-/- mice of both sexes was substantially lower than in wild type and Tpst1-/- mice. Anti-sulfotyrosine Western blots of salivary gland extracts and saliva showed no differences between wild type, Tpst1-/-, and Tpst2-/- mice, suggesting that the salivary gland hypofunction is due to factor(s) extrinsic to the salivary glands. Finally, we found that all indicators of hypothyroidism (serum T4, body weight) and salivary gland hypofunction (salivary flow, salivary α-amylase activity, histological changes) were restored to normal or near normal by thyroid hormone supplementation.Conclusions/SignificanceOur findings conclusively demonstrate that low body weight and salivary gland hypofunction in Tpst2-/- mice is due solely to primary hypothyroidism.
Highlights
Tyrosine O-sulfation is a posttranslational modification catalysed by tyrosylprotein sulfotransferases (TPSTs) that mediate the transfer of a sulfuryl group from the sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to the hydroxyl group of peptidyl-tyrosine to form a tyrosine O4-sulfate ester and 3’, 5’-ADP [1]
We reported that Tpst2-/- mice have mild-moderate primary hypothyroidism, whereas Tpst1-/- mice are euthyroid [18] consistent with the observations by Sasaki et al that a spontaneous mutation in the Tpst2 gene is responsible for an autosomal recessive form of primary hypothyroidism in the grt/grt mouse [19]
We previously reported that Tpst2-/- mice on a 129S6 genetic background have mild-moderate primary hypothyroidism, whereas Tpst1-/- mice are euthyroid [18]
Summary
Tyrosine O-sulfation is a posttranslational modification catalysed by tyrosylprotein sulfotransferases (TPSTs) that mediate the transfer of a sulfuryl group from the sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to the hydroxyl group of peptidyl-tyrosine to form a tyrosine O4-sulfate ester and 3’, 5’-ADP [1]. While using magnetic resonance imaging (MRI) to look at the thyroid gland we noticed that the salivary glands in Tpst2-/mice appeared smaller than in wild type mice. This prompted a detailed analysis to compare salivary gland structure and function in wild type, Tpst1-/-, and Tpst2 -/- mice. Methodology/Principal Findings: Quantitative MRI imaging documented that salivary glands in Tpst2-/- females were ≈ 30% smaller than wild type or Tpst1-/- mice and that the granular convoluted tubules in Tpst2-/submandibular glands were less prominent and were almost completely devoid of exocrine secretory granules compared to glands from wild type or Tpst1-/- mice. Conclusions/Significance: Our findings conclusively demonstrate that low body weight and salivary gland hypofunction in Tpst2-/- mice is due solely to primary hypothyroidism
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