کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8259791 | 1534645 | 2015 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding
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کلمات کلیدی
IRE1XBP1GRP94BiP - BIPinositol-requiring enzyme 1 - آنزیم مورد نیاز inositol 1endoplasmic reticulum stress response - اندوپلاسمی رتیکولوم استرس پاسخX-box binding protein-1 - جعبه اتصال پروتئین -1endoplasmic reticulum - شبکه آندوپلاسمی Protein misfolding - غلظت پروتئینLipase - لیپازPancreatic triglyceride lipase - لیپاز تری گلیسرید پانکراسFat digestion - هضم چربیImmunoglobulin binding protein - پروتئین اتصال ایمونوگلوبولین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Congenital pancreatic triglyceride lipase (PNLIP) deficiency is a rare disorder with uncertain genetic background as most cases were described before gene sequencing was readily available. Recently, two brothers with PNLIP deficiency were found to carry a homozygous missense mutation, c.662CÂ >Â T (p.T221M) in the PNLIP gene (J. Lipid Res. 2014. 55:307-312). Molecular modeling suggested the substitution would change the orientation of residues in the catalytic site and disrupt the function of p.T221M PNLIP. To test the effect of the p.T221M mutation on PNLIP function, we expressed wild-type and p.T221M PNLIP in human embryonic kidney (HEK) 293A cells and dexamethasone-differentiated AR42J rat acinar cells. In both cellular models, wild-type PNLIP was secreted into the conditioned medium where it was readily detectable by protein staining, immunoblot or lipase activity assays. In contrast, mutant p.T221M was not secreted into the medium, but it was present in cell lysates where it accumulated in the insoluble fraction. Intracellular retention of mutant p.T221M resulted in endoplasmic reticulum (ER) stress as measured by elevated XBP1 splicing and increased levels of ER chaperones. Our results demonstrate that the presence of methionine at position 221 in the PNLIP protein sequence causes misfolding and aggregation of the p.T221M mutant inside the cell. The consequent loss of enzyme secretion adequately explains the clinical phenotype of PNLIP deficiency reported for homozygous carriers of p.T221M. Furthermore, the ability of mutant p.T221M to induce ER stress suggests that this form of PNLIP deficiency might cause acinar cell damage as well.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1852, Issue 7, July 2015, Pages 1372-1379
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1852, Issue 7, July 2015, Pages 1372-1379
نویسندگان
András Szabó, Xunjun Xiao, Margaret Haughney, Alyssa Spector, Miklós Sahin-Tóth, Mark E. Lowe,