Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes.
Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes.
复制标题
前胰岛素原信号肽的裂解受损与常染色体显性糖尿病有关
作者：
Liu M;Lara-Lemus R;Shan SO;Wright J;Haataja L;Barbetti F;Guo H;Larkin D;Arvan P
近年来，有报道称前胰岛素原信号肽（SP）裂解位点上游的错义突变导致突变型INS基因诱导的青年糖尿病（MIDY）。我们的目的是通过代谢标记和胰岛素原输出、胰岛素和C肽产生的测定来了解分子发病机制，以检查胰岛素生物合成的最早期事件，突出β细胞衰竭的分子机制以及可能改善MIDY综合征的新策略。我们发现，而preproinsulin-A（SP23）S被有效地切割，产生真正的胰岛素原和胰岛素，preproinsulin-A（SP24）D是无效的切割在一个不适当的网站，产生两个亚群的分子。两者都显示受损的氧化折叠，并保留在内质网（ER）。前胰岛素原-A（SP24）D也阻断共表达的野生型胰岛素原的ER退出，解释其显性负性行为。在ER-氧化还原蛋白-1表达增加后，前胰岛素原-A（SP24）D仍然被阻断，但野生型胰岛素原的氧化折叠得到改善，加速其ER输出并增加野生型胰岛素的产生。我们的结论是SP切割的效率与（前）胰岛素原的氧化有关。反过来，受损（前）胰岛素原氧化影响ER出口的突变体以及共表达的野生型胰岛素原。改善野生型胰岛素原的氧化折叠可能提供一种可行的方法来挽救MIDY患者的胰岛素产生。
Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY.
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DOI：
10.1083/jcb.103.6.2263
发表时间：
1986-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Eskridge EM;Shields D
通讯作者：
Shields D
影响因子：
--
作者：
Boesgaard TW;Pruhova S;Andersson EA;Cinek O;Obermannova B;Lauenborg J;Damm P;Bergholdt R;Pociot F;Pisinger C;Barbetti F;Lebl J;Pedersen O;Hansen T
通讯作者：
Hansen T
影响因子：
7.7
作者：
Hodish I;Absood A;Liu L;Liu M;Haataja L;Larkin D;Al-Khafaji A;Zaki A;Arvan P
通讯作者：
Arvan P
人类胰岛素基因的七种突变与永久性新生儿/婴幼儿糖尿病有关
影响因子：
15.9
作者：
Colombo, Carlo;Porzio, Ottavia;Barbetti, Fabrizio
通讯作者：
Barbetti, Fabrizio
DOI：
10.1089/clo.2008.0020
发表时间：
2008-12-01
期刊：
CLONING AND STEM CELLS
影响因子：
--
作者：
Miyamoto, Kei;Yamashita, Teruyoshi;Imai, Hiroshi
通讯作者：
Imai, Hiroshi