Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances β-Cell Susceptibility to Palmitate. Mol Cell Biol 2018 Apr 15;38(8)
Date
01/31/2018Pubmed ID
29378831Pubmed Central ID
PMC5879465DOI
10.1128/MCB.00680-17Scopus ID
2-s2.0-85044766344 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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 β-cell damage. In this report, we identify a role for lysosomal protein degradation as a mechanism by which β 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 β cells from excess palmitate.
Author List
Baldwin AC, Naatz A, Bohnsack RN, Bartosiak JT, Oleson BJ, Hansen PA, Dahms NM, Corbett JAAuthors
Richard N. Bohnsack Research Scientist I in the Biochemistry department at Medical College of WisconsinJohn A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin
Nancy M. Dahms PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCations
Cattle
Cell Line
Cell Survival
Endocytosis
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Golgi Apparatus
HEK293 Cells
Humans
Insulin
Insulin-Secreting Cells
Lipoylation
Lysosomes
Male
Mannosephosphates
Palmitates
Protein Transport
Rats
Rats, Sprague-Dawley
