N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic.
N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic.
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DOI：
10.1083/jcb.200808124
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发表时间：
2009-03-23
期刊：
影响因子：
--
通讯作者：
Lukacs GL
中科院分区：
文献类型：
--
作者：
Glozman R;Okiyoneda T;Mulvihill CM;Rini JM;Barriere H;Lukacs GL
N-糖基化是一种常见的共翻译修饰，被认为对糖蛋白的质膜表达至关重要，其通过经由凝集素样分子伴侣将蛋白质靶向ER折叠循环来增强蛋白质折叠、运输和稳定性。在这项研究中，我们表明，N-聚糖，特别是核心聚糖，提高生产性折叠和构象稳定性的多位膜蛋白，囊性纤维化跨膜传导调节（CFTR），独立的凝集素样分子伴侣。缺陷的N-糖基化通过损害CFTR的早期分泌和内吞运输来降低细胞表面表达。聚糖缺陷型CFTR的构象不稳定诱导泛素化，导致从细胞表面快速消除。泛素化的CFTR针对溶酶体降解，而不是早期内体中的内吞再循环，其由转运所需的泛素结合内体分选复合物（ESCRT）衔接子Hrs（肝细胞生长因子调节的酪氨酸激酶底物）和TSG 101介导。这些结果表明，共翻译的N-糖基化可以发挥一个伴侣独立的profolding变化的能量CFTR在体内，以及概述了一个范例的外周运输缺陷的膜蛋白受损的糖基化。
N-glycosylation, a common cotranslational modification, is thought to be critical for plasma membrane expression of glycoproteins by enhancing protein folding, trafficking, and stability through targeting them to the ER folding cycles via lectin-like chaperones. In this study, we show that N-glycans, specifically core glycans, enhance the productive folding and conformational stability of a polytopic membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), independently of lectin-like chaperones. Defective N-glycosylation reduces cell surface expression by impairing both early secretory and endocytic traffic of CFTR. Conformational destabilization of the glycan-deficient CFTR induces ubiquitination, leading to rapid elimination from the cell surface. Ubiquitinated CFTR is directed to lysosomal degradation instead of endocytic recycling in early endosomes mediated by ubiquitin-binding endosomal sorting complex required for transport (ESCRT) adaptors Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) and TSG101. These results suggest that cotranslational N-glycosylation can exert a chaperone-independent profolding change in the energetic of CFTR in vivo as well as outline a paradigm for the peripheral trafficking defect of membrane proteins with impaired glycosylation.
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影响因子：
4
作者：
Chang XB;Mengos A;Hou YX;Cui L;Jensen TJ;Aleksandrov A;Riordan JR;Gentzsch M
通讯作者：
Gentzsch M
影响因子：
5.6
作者：
Cui, Liying;Aleksandrov, Luba;Riordan, John R.
通讯作者：
Riordan, John R.
影响因子：
3
作者：
Hämmerle, MM;Aleksandrov, AA;Riordan, JR
通讯作者：
Riordan, JR
影响因子：
16.8
作者：
Du, K;Sharma, M;Lukacs, GL
通讯作者：
Lukacs, GL
DOI：
10.1006/bbrc.1999.1963
发表时间：
2000-01-07
影响因子：
3.1
作者：
Fujita, K;Tanaka, N;Takegawa, K
通讯作者：
Takegawa, K