Loss of Trabid, a new negative regulator of the drosophila immune-deficiency pathway at the level of TAK1, reduces life span.
Loss of Trabid, a new negative regulator of the drosophila immune-deficiency pathway at the level of TAK1, reduces life span.
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DOI：
10.1371/journal.pgen.1004117
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Ligoxygakis P
中科院分区：
文献类型：
--
作者：
Fernando MD;Kounatidis I;Ligoxygakis P
果蝇免疫缺陷（IMD）通路中一个相对未开发的联系是TGF-β激活激酶1（TAK 1），它触发免疫和细胞凋亡。在细胞培养筛选中，我们确定了142位的赖氨酸是TAK 1的K63连接的泛素受体位点，是信号传导所需的。此外，156位的赖氨酸作为K48连接的泛素受体位点发挥作用，这也是TAK 1活性所必需的。去泛素化酶Trabid与TAK 1相互作用，减少免疫信号输出和K63连接的泛素化。Trabid活性需要三个串联Np 14锌指和位置518处的催化半胱氨酸。缺乏Trabid的果蝇由于IMD在全身和肠道中的慢性激活而寿命缩短，其中稳态被破坏。TAK 1相关结合蛋白2（TAB 2）通过其锌指结构域与TAK 1-Trabid相互作用连接，所述锌指结构域安抚TAK 1信号。这些结果表明，一个复杂的和多层次的机制，调节TAK 1活性和调节其免疫信号。免疫反应的慢性激活导致健康问题，包括胃肠道感染、代谢失衡和可能导致结直肠癌的炎症性肠病。其核心是在先天免疫应答期间核因子-κB（NF-κB）的活化/限制的平衡。为了研究通过NF-κB的信号传导，我们使用果蝇作为遗传学上易于处理的模型系统，该模型系统反映了人类生物学（由于果蝇和哺乳动物先天免疫之间的进化保守性），同时降低了感兴趣的人类疾病的复杂性。我们发现了一个新的果蝇NF-κB通路负调控因子Trabid。它的丢失释放了该途径，并导致肠道和整个苍蝇中的组成性免疫激活。这种自发的免疫激活在没有感染的情况下缩短了寿命，特别是当它与另一种已知的相同途径的负调节因子（一种名为皮尔克的蛋白质）的丢失相结合时。发现皮尔克;trabid双突变体中肠道中的干细胞活性显著增加，因为肠道试图平衡肠上皮细胞损失。Trabid在TGF-β激活激酶1（TAK 1）水平起作用，这会触发免疫和细胞死亡。
A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalling. Moreover, Lysine at position 156 functioned as a K48-linked Ubiquitin acceptor site, also necessary for TAK1 activity. The deubiquitinase Trabid interacted with TAK1, reducing immune signalling output and K63-linked ubiquitination. The three tandem Npl4 Zinc Fingers and the catalytic Cysteine at position 518 were required for Trabid activity. Flies deficient for Trabid had a reduced life span due to chronic activation of IMD both systemically as well as in their gut where homeostasis was disrupted. The TAK1-associated Binding Protein 2 (TAB2) was linked with the TAK1-Trabid interaction through its Zinc finger domain that pacified the TAK1 signal. These results indicate an elaborate and multi-tiered mechanism for regulating TAK1 activity and modulating its immune signal. Chronic activation of immune responses results in health problems including gastrointestinal infections, metabolic imbalances and inflammatory bowel diseases that may lead to colorectal cancer. Central to this, is the balance of activation/restriction of nuclear factor-κB (NF-κB) during innate immune responses. To study signaling through NF-κB, we use the fruit fly Drosophila melanogaster as a genetically tractable model system that reflects human biology (due to the evolutionary conservation between innate immunity in flies and mammals), while reducing the complexity of the human disease of interest. We have found a new negative regulator of the Drosophila NF-κB pathway named Trabid. Its loss released the pathway and resulted in constitutive immune activation both in the gut as well as in the whole fly. This spontaneous immune activation reduced life span in the absence of infection, especially when it was combined with loss of another known negative regulator of the same pathway, a protein named Pirk. Stem cell activity in the gut in a pirk;trabid double mutant was found to be significantly increased, as the gut was trying to balance enterocyte loss. Trabid was acting at the level of TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and cell death.
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影响因子：
30.5
作者：
Kaneko, Takashi;Yano, Tamaki;Silverman, Neal
通讯作者：
Silverman, Neal
DOI：
10.1073/pnas.0812022106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Erturk-Hasdemir, Deniz;Broemer, Meike;Silverman, Neal
通讯作者：
Silverman, Neal
影响因子：
7.7
作者：
Balakirev, MY;Tcherniuk, SO;Chroboczek, J
通讯作者：
Chroboczek, J
影响因子：
4.8
作者：
Besse, Arnaud;Lamothe, Betty;Darnay, Bryant G.
通讯作者：
Darnay, Bryant G.
影响因子：
9.2
作者：
Leulier, F;Vidal, S;Lemaitre, B
通讯作者：
Lemaitre, B