Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals.
Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals.
复制标题
DOI：
10.1371/journal.pbio.1001505
复制
发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Eaton S
中科院分区：
文献类型：
--
作者：
Palm W;Swierczynska MM;Kumari V;Ehrhart-Bornstein M;Bornstein SR;Eaton S
我们确定了两种不同的Hh分泌形式与哺乳动物和苍蝇产生的互补信号传导活动：一个甾醇修饰和脂蛋白相关，另一个缺乏甾醇修饰。Hedgehog（Hh）蛋白控制动物的发育和组织内稳态。它们通过调节Gli/Cubitus interruptus（Ci）转录因子的加工、稳定性和激活来激活基因表达。尽管在加工过程中与固醇共价连接，但Hh蛋白质仍被分泌并通过组织传播。已提出多种机制以不同形式释放Hh蛋白;在果蝇中，脂蛋白促进长距离Hh动员，但也含有抑制该途径的脂质。在这里，我们表明，哺乳动物脂蛋白保守的作用，在刺猬（嘘）的释放和途径的抑制。我们证明，脂蛋白相关形式的Hh和Shh特异性阻断脂蛋白介导的通路抑制。我们还确定了第二种保守的释放形式，它不是固醇修饰的，可以独立于脂蛋白释放（Hh-N*/Shh-N*）。脂蛋白相关的Hh/Shh和Hh-N*/Shh-N* 具有互补和协同作用。在果蝇翅成虫盘，脂蛋白相关的Hh增加全长Ci的量，但不足以激活靶基因。然而，少量的非固醇修饰的Hh与脂蛋白相关的Hh协同作用，以完全激活该途径并允许靶基因表达。具有不同信号传导活性的Hh分泌形式的存在表明了产生多种Hh反应的新机制。Hedgehog（Hh）蛋白是一种保守的分泌型信号分子，调节胚胎发育和成体组织的稳态。异位Hh信号传导促进肿瘤发生，并且许多肿瘤分泌哺乳动物Sonic Hedgehog（Shh）支持它们的生长和存活。由于Hh蛋白被甾醇和棕榈酸酯共价修饰，因此需要特定的机制将其从细胞膜释放。在这里，我们表明，不同的苍蝇和哺乳动物细胞类型，包括Shh依赖性癌细胞，释放脂质修饰的Hh/Shh的脂蛋白-循环中的主要脂质载体。脂蛋白代谢紊乱是代谢综合征的一个标志，与许多组织病理学和癌症风险升高有关。我们发现，果蝇和哺乳动物脂蛋白积极行动，动员脂质修饰的Hh蛋白，但也含有脂质抑制的途径时，Hh/Shh是缺席的。Hh/Shh与脂蛋白的关联中和了它们在两种生物体中的抑制作用。我们还发现，许多细胞释放第二种形式的Hh/Shh独立于缺乏固醇修饰的脂蛋白。这种形式不能克服脂蛋白介导的抑制，但在脂蛋白相关的Hh/Shh存在下进一步激活该途径。具有不同活性的多种释放形式的存在表明了对Hh配体产生不同反应的新的保守机制。我们的数据还表明，扰动Hh信号可能有助于与脂蛋白功能障碍相关的人类病理学。
We identify two distinct Hh secretion forms with complementary signaling activities produced in both mammals and flies: one sterol-modified and lipoprotein-associated, and another lacking sterol modification. Hedgehog (Hh) proteins control animal development and tissue homeostasis. They activate gene expression by regulating processing, stability, and activation of Gli/Cubitus interruptus (Ci) transcription factors. Hh proteins are secreted and spread through tissue, despite becoming covalently linked to sterol during processing. Multiple mechanisms have been proposed to release Hh proteins in distinct forms; in Drosophila, lipoproteins facilitate long-range Hh mobilization but also contain lipids that repress the pathway. Here, we show that mammalian lipoproteins have conserved roles in Sonic Hedgehog (Shh) release and pathway repression. We demonstrate that lipoprotein-associated forms of Hh and Shh specifically block lipoprotein-mediated pathway inhibition. We also identify a second conserved release form that is not sterol-modified and can be released independently of lipoproteins (Hh-N*/Shh-N*). Lipoprotein-associated Hh/Shh and Hh-N*/Shh-N* have complementary and synergistic functions. In Drosophila wing imaginal discs, lipoprotein-associated Hh increases the amount of full-length Ci, but is insufficient for target gene activation. However, small amounts of non-sterol-modified Hh synergize with lipoprotein-associated Hh to fully activate the pathway and allow target gene expression. The existence of Hh secretion forms with distinct signaling activities suggests a novel mechanism for generating a diversity of Hh responses. Hedgehog (Hh) proteins are conserved secreted signaling molecules that regulate embryonic development and adult tissue homeostasis. Ectopic Hh signaling promotes tumorigenesis, and secretion of mammalian Sonic Hedgehog (Shh) by many tumors supports their growth and survival. As Hh proteins are covalently modified by sterol and palmitate, specific mechanisms are required to release them from cell membranes. Here, we show that different fly and mammalian cell types, including Shh-dependent cancer cells, release lipid-modified Hh/Shh on lipoproteins—the major lipid carriers in circulation. Perturbed lipoprotein metabolism is a hallmark of metabolic syndrome, which is associated with many tissue pathologies and an elevated cancer risk. We show that Drosophila and mammalian lipoproteins act positively to mobilize lipid-modified Hh proteins, but also contain lipids that repress the pathway when Hh/Shh is absent. Association of Hh/Shh with lipoproteins neutralizes their inhibitory effect in both organisms. We also find that many cells release a second form of Hh/Shh independently of lipoproteins that lacks sterol modification. This form cannot overcome lipoprotein-mediated repression but further activates the pathway in the presence of lipoprotein-associated Hh/Shh. The existence of multiple release forms with different activities suggests novel conserved mechanisms for generating diverse responses to Hh ligands. Our data also suggest that perturbed Hh signaling could contribute to human pathologies associated with lipoprotein dysfunction.
登录
查看更多内容
DOI：
10.1111/tra.12016
发表时间：
2013-01
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Beckett K;Monier S;Palmer L;Alexandre C;Green H;Bonneil E;Raposo G;Thibault P;Le Borgne R;Vincent JP
通讯作者：
Vincent JP
影响因子：
11.8
作者：
Gallet, A;Rodriguez, R;Therond, PP
通讯作者：
Therond, PP
影响因子：
5.3
作者：
Brankatschk, Marko;Eaton, Suzanne
通讯作者：
Eaton, Suzanne
影响因子：
11.8
作者：
Christ, Annabel;Christa, Anna;Hammes, Annette
通讯作者：
Hammes, Annette
影响因子：
4.6
作者：
Dubois, Laurence;Enriquez, Jonathan;Vincent, Alain
通讯作者：
Vincent, Alain