O-fucosylation of DLL3 is required for its function during somitogenesis.
O-fucosylation of DLL3 is required for its function during somitogenesis.
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DOI：
10.1371/journal.pone.0123776
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gossler A
中科院分区：
文献类型：
--
作者：
Serth K;Schuster-Gossler K;Kremmer E;Hansen B;Marohn-Köhn B;Gossler A
Delta-like 3（DLL 3）是Notch配体的DSL家族的成员。与DLL 1和DLL 4（小鼠中的其他Delta样蛋白）相反，DLL 3不与Notch反式结合，也不激活该受体，但在体外显示出对Notch信号传导的顺式相互作用和顺式抑制特性。小鼠中DSL蛋白DLL 3的缺失导致严重的体节图案化缺陷，其与缺乏Lunatic fringe（LFNG）（一种参与修饰Notch信号传导的糖基转移酶）的小鼠中的缺陷几乎无法区分。DLL 3与LFNG一样位于trans-Golgi内，但其生化功能尚不清楚。在这里，我们表明i）两种蛋白质相互作用，ii）DLL 3的表皮生长因子样重复序列2和5在POFUT 1的共有位点处被O-岩藻糖基化，以及iii）在体外被FNG蛋白质进一步修饰。Dll 3和Lfng无效突变的双纯合胚胎在表型上与支持潜在共同功能的单突变体难以区分。DLL 3中O-岩藻糖基化位点的突变不会破坏DLL 3与LFNG或全长Notch 1或DLL 1的相互作用，并且O-岩藻糖基化缺陷DLL 3仍然可以在体外顺式抑制Notch。然而，与野生型DLL 3相反，0-岩藻糖基化缺陷型DLL 3不能补偿胚胎中体节发生期间内源性DLL 3的损失。总之，我们的结果表明，在培养细胞中观察到的DLL 3的顺式抑制活性可能不能完全反映其假定的基本生理特性，表明DLL 3和LFNG一起作用，并强烈支持通过O-连接的岩藻糖修饰DLL 3对于其在体节发生期间的功能是必不可少的。
Delta-like 3 (DLL3) is a member of the DSL family of Notch ligands in amniotes. In contrast to DLL1 and DLL4, the other Delta-like proteins in the mouse, DLL3 does not bind in trans to Notch and does not activate the receptor, but shows cis-interaction and cis-inhibitory properties on Notch signaling in vitro. Loss of the DSL protein DLL3 in the mouse results in severe somite patterning defects, which are virtually indistinguishable from the defects in mice that lack lunatic fringe (LFNG), a glycosyltransferase involved in modifying Notch signaling. Like LFNG, DLL3 is located within the trans-Golgi, however, its biochemical function is still unclear. Here, we show that i) both proteins interact, ii) epidermal growth factor like repeats 2 and 5 of DLL3 are O-fucosylated at consensus sites for POFUT1, and iii) further modified by FNG proteins in vitro. Embryos double homozygous for null mutations in Dll3 and Lfng are phenotypically indistinguishable from the single mutants supporting a potential common function. Mutation of the O-fucosylation sites in DLL3 does not disrupt the interaction of DLL3 with LFNG or full length Notch1or DLL1, and O-fucosylation-deficient DLL3 can still inhibit Notch in cis in vitro. However, in contrast to wild type DLL3, O-fucosylation-deficient DLL3 cannot compensate for the loss of endogenous DLL3 during somitogenesis in the embryo. Together our results suggest that the cis-inhibitory activity of DLL3 observed in cultured cells might not fully reflect its assumed essential physiological property, suggest that DLL3 and LFNG act together, and strongly supports that modification of DLL3 by O-linked fucose is essential for its function during somitogenesis.
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DOI：
10.1083/jcb.200702009
发表时间：
2007-07-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Geffers I;Serth K;Chapman G;Jaekel R;Schuster-Gossler K;Cordes R;Sparrow DB;Kremmer E;Dunwoodie SL;Klein T;Gossler A
通讯作者：
Gossler A
DOI：
10.1073/pnas.93.17.9067
发表时间：
1996-08-20
影响因子：
11.1
作者：
Bronson, SK;Plaehn, EG;Smithies, O
通讯作者：
Smithies, O
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
2.6
作者：
Beckers, J;Caron, A;Gossler, A
通讯作者：
Gossler, A
影响因子：
64.5
作者：
Blaumueller, CM;Qi, HL;ArtavanisTsakonas, S
通讯作者：
ArtavanisTsakonas, S