NF-κB的訊息傳導非常重要，一旦 NF-κB不正當的活化時會導致免疫調節失調，而產生自體免疫疾病。因此，參與這條訊息傳遞鏈及其調節蛋白都非常重要。包含其中心酵素 IKK複合體與線性長鍊泛素鏈。然而目前針對其上下游及調節蛋白及 ABIN1與 NEMO是如何與長鏈線性泛素鏈調節 NF-κB的機制仍不清楚。因此，本研究藉由生化與結構解析NEMO與 TRAF6的關係，並得到 IBα與 IKKβ NEMO的複合物之蛋白質結晶，以及 UBAN蛋白與線性泛素鏈之結構，來探討這些調節分子之功能。我們解出了 ABIN1與線性泛素鏈的結構，並以生化分析解 釋線性泛素鏈的角色為一個分子平台，使許多調節蛋白聚集，進而更快速地傳遞訊息且調控 NF-κB。此外，藉由點突變的實驗，我們也驗證了 ABIN1和線性泛素鏈鍵結之重要氨基酸位點，且發現那些造成疾病之 ABIN1蛋白上的點突變都是位重要的鍵結位置。另外，本研究亦解析了 NEMO-ZnF與ABIN1-AHD domain之功能。從了解這些參與 NF-κB調節之蛋白，能幫助我們去解決與 NF-κB 失衡導致的相關疾病。

Nuclear factor κB (NF-κB) transcription factors are master regulators of inflammatory, immune, and apoptotic responses. Excessive NF-κB activity has been linked to inflammatory disorders and autoimmune diseases. Therefore, the molecules involved in this signaling cascade are vital for cellular homeostasis. A central kinase termed the IKK complex, which is composed of IKKα, IKKβ, and a regulatory subunit called NEMO plays a central role in the activation of NF-κB. The linear (M1)-linked poly-ubiquitin tightly regulates NF-κB through interacting with UBAN (Ub-binding domain in ABIN proteins and NEMO) proteins, including NEMO and ABIN1. However, the recognition mechanism of each interaction between these molecules in the NF-κB signaling pathway is still undetermined. Hence, we utilized biochemical and structural means to analyze the correlation between TRAF6 with NEMO, IKKβ with IκBα, and UBAN with linear poly-ubiquitin. Also, we discuss the domain function of NEMO-ZnF and ABIN1-AHD. Of them, we successfully identified three crystal structures of the ABIN1-UBAN and the linear poly-ubiquitin chains. Based on a and biochemical analyses, we found that the long linear poly-ubiquitin chains serve as a platform for a high-order assembly of the UBAN proteins to mediate NF-κB activation. In addition, we identified important interacting sites and clarified disease-causing mutations that disrupt the interaction between ABIN1 and ubiquitin. We also demonstrated that although the affinity between ABIN1 and the K63 linked poly-ubiquitin is weak, their interaction sites are similar with ABIN1 and linear poly-ubiquitin. Collectively, this study provides insights into NF-κB regulation and may serve as a foundation for further studies. Understanding the NF-κB signaling pathway may facilitate designing novel therapeutics.

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