Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances β-Cell Susceptibility to Palmitate

被引:3
|
作者
Baldwin, Aaron C. [1 ]
Naatz, Aaron [1 ]
Bohnsack, Richard N. [1 ]
Bartosiak, Jacob T. [1 ]
Oleson, Bryndon J. [1 ]
Hansen, Polly A. [1 ]
Dahms, Nancy M. [1 ]
Corbett, John A. [1 ]
机构
[1] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA
基金
美国国家卫生研究院;
关键词
beta cell; islet; CI-MPR; lysosome; palmitate; free fatty acid; diabetes; ER stress; palmitoylation; ENDOPLASMIC-RETICULUM STRESS; ER STRESS; PROTEIN PALMITOYLATION; NITRIC-OXIDE; FATTY-ACIDS; AUTOPHAGY; DYSFUNCTION; GLUCOSE; FAILURE; GLUCOLIPOTOXICITY;
D O I
10.1128/MCB.00680-17
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Palmitate attenuates insulin secretion and reduces the viability of insulin-producing cells. Previous studies identified the aberrant palmitoylation or mispalmitoylation of proteins as one mechanism by which palmitate causes beta-cell damage. In this report, we identify a role for lysosomal protein degradation as a mechanism by which beta cells defend themselves against excess palmitate. The cation-independent mannose 6-phosphate receptor (CI-MPR) is responsible for the trafficking of mannose 6-phosphate-tagged proteins to lysosomes via Golgi sorting and from extracellular locations through endocytosis. RINm5F cells, which are highly sensitive to palmitate, lack CI-MPR. The reconstitution of CI-MPR expression attenuates the induction of endoplasmic reticulum (ER) stress and the toxic effects of palmitate on RINm5F cell viability. INS832/13 cells express CI-MPR and are resistant to the palmitate-mediated loss of cell viability. The reduction of CI-MPR expression increases the sensitivity of INS832/13 cells to the toxic effects of palmitate treatment. The inhibition of lysosomal acid hydrolase activity by weak base treatment of islets under glucolipotoxic conditions causes islet degeneration that is prevented by the inhibition of protein palmitoylation. These findings indicate that defects in lysosomal function lead to the enhanced sensitivity of insulin-producing cells to palmitate and support a role for normal lysosomal function in the protection of beta cells from excess palmitate.
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页数:17
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