台灣留學生出席國際會議補助

2010年4月14日星期三

Kinetic control of negative feedback regulators of NF-kB/RelA determines their pathogen- and cytokine-receptor signaling specificity

論文發表人:史逢聖 (加州大學聖地牙哥分校 生化所博士班)

 

http://www.keystonesymposia.org/

 

細胞中的訊息傳遞網絡包含了許多參與負回饋機制的分子, 這些分子可能擁有重複的功能或者具有專一性。在 NF-kB 的傳遞單元裡 , 不僅 IkBa 參與負回饋機的反應,  新發現的抑制分子 IkBd 的蛋白質表現也受免疫反應激發因子而增加。為了檢驗 IkBd 在免疫反應訊息傳遞中的功能, 我門利用數學方程式模擬了包含四個 IkB 抑制分子的 NF-kB 傳導單元, 並且發展出以電腦程式分析基因表現型的方法。我們發現 IkBd 相同於 IkBa , 參與負回饋機制反應, 但兩者對於不同的免疫反應激發因子具有專一性。IkBd 減緩經由病原體接觸受器 (TLR) 所引起的持續反應 , 而具有快速反應特性的 IkBa , 其主要功能則為決定細胞激素引起 NF-kB 活性的時間曲線。除此之外 , 當活化 NF-kB 功能的細胞激素腫瘤壞死因子 (TNF) 從實驗鼠中被移除 , 過去因缺伐抑制分子 IkBa 導致過度免疫反應而致死的突變老鼠 , 在此實驗中可維持其生命力。最後 , 我們發現 IkBd 因具有較長的蛋白質降解週期 , 可統整細胞的免疫反應記憶 , 並減弱 NF-kB的反應。

 

Mammalian signaling networks contain an abundance of negative feedback regulators that may have overlapping ("fail-safe") or specific functions.  Within the NF-kB signaling module, IkBa is known as a negative feedback regulator, but the newly characterized inhibitor IkBd is also inducibly expressed in response to inflammatory stimuli.  To examine IkBd's roles in inflammatory signaling, we mathematically modeled the four-IkB-containing NF-kB signaling module and developed a computational phenotyping methodology of general applicability. We found that IkBd, like IkBa, can provide negative feedback, but each functions stimulus-specifically.  Whereas IkBd attenuates persistent, pathogen-triggered signals mediated by TLRs, the more prominent IkBa does not.  Instead, IkBa, which functions more rapidly, is primarily involved in determining the temporal profile of NF-kB signaling in response to cytokines that serve intercellular communication.  Indeed, when removing the inducing cytokine stimulus by compound deficiency of the tnf gene, we found that the lethality of ikba-/- mouse was rescued.  Finally, we found that IkBd provides signaling memory owing to its long half-life; it integrates the inflammatory history of the cell to dampen NF-kB responsiveness during sequential stimulation events.