The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity.
The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity.
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DOI：
10.1016/j.jbc.2021.100661
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Fjeld K
中科院分区：
文献类型：
--
作者：
Gravdal A;Xiao X;Cnop M;El Jellas K;Johansson S;Njølstad PR;Lowe ME;Johansson BB;Molven A;Fjeld K
基因组中数量可变的串联重复序列(VNTR)可能会产生导致人类疾病的功能后果。CEL基因就是这种情况，它在胰腺腺泡细胞中特异表达，编码消化酶羧酸酯脂肪酶。CEL第一段(DEL1)或第四段(DEL4)中罕见的单碱基缺失(DELs)可导致青年8型糖尿病(MODY8)，这是一种以胰腺外分泌功能障碍和糖尿病为特征的遗传性疾病。对DEL1变异体的研究表明，MODY8是由CEL蛋白错误折叠和聚集启动的。然而，目前尚不清楚CEL VNTR中单碱基缺失的位置如何影响蛋白质的致病特性。在这里，我们研究了四种自然发生的CEL变体，它们是由不同VNTR片段(DEL1、DEL4、DEL9和DEL13)的单碱基缺失引起的。在人胚胎肾293细胞中，只有DEL1和DEL4与正常CEL蛋白相比，分泌显著减少，细胞内聚集增加，内质网应激增加。在所有的Del变异体中，O-糖基化水平都受到影响。此外，所有突变体都具有与正常CEL相当的酶活性。我们得出结论，最长的异常蛋白尾巴，由近端VNTR片段的单碱基缺失引起，具有最高的致病潜力，这解释了为什么在MODY8患者中观察到DEL1和DEL4，而不是DEL9和DEL13。这些发现进一步支持CEL突变通过蛋白质错误折叠和蛋白质毒性导致胰腺疾病的观点，导致内质网应激和未折叠蛋白质反应的激活。
Variable number of tandem repeat (VNTR) sequences in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which is specifically expressed in pancreatic acinar cells and encodes the digestive enzyme carboxyl ester lipase. Rare single-base deletions (DELs) within the first (DEL1) or fourth (DEL4) VNTR segment of CEL cause maturity-onset diabetes of the young, type 8 (MODY8), an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Studies on the DEL1 variant have suggested that MODY8 is initiated by CEL protein misfolding and aggregation. However, it is unclear how the position of single-base deletions within the CEL VNTR affects pathogenic properties of the protein. Here, we investigated four naturally occurring CEL variants, arising from single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, and DEL13). When the four variants were expressed in human embryonic kidney 293 cells, only DEL1 and DEL4 led to significantly reduced secretion, increased intracellular aggregation, and increased endoplasmic reticulum stress compared with normal CEL protein. The level of O-glycosylation was affected in all DEL variants. Moreover, all variants had enzymatic activity comparable with that of normal CEL. We conclude that the longest aberrant protein tails, resulting from single-base deletions in the proximal VNTR segments, have highest pathogenic potential, explaining why DEL1 and DEL4 but not DEL9 and DEL13 have been observed in patients with MODY8. These findings further support the view that CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to endoplasmic reticulum stress and activation of the unfolded protein response.
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影响因子：
3.7
作者：
Fjeld, Karianne;Beer, Sebastian;Rosendahl, Jonas
通讯作者：
Rosendahl, Jonas
DOI：
10.1111/j.1432-1033.1995.tb20327.x
发表时间：
1995-03-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BLACKBERG, L;STROMQVIST, M;HERNELL, O
通讯作者：
HERNELL, O
影响因子：
7.7
作者：
Cai CQ;Zhang T;Breslin MB;Giraud M;Lan MS
通讯作者：
Lan MS
DOI：
10.1038/nsb961
发表时间：
2003-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Lee, S;Eisenberg, D
通讯作者：
Eisenberg, D
DOI：
10.1046/j.0014-2956.2001.02666.x
发表时间：
2002-02-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Lindquist, S;Bläckberg, L;Hernell, O
通讯作者：
Hernell, O