抑酶會直接與細胞內多胺生合成的關鍵酵素鳥胺酸脫羧酶結合形成異質二聚體，進而使得鳥胺酸脫羧酶同質雙聚合體分離而失去活性並且使鳥胺酸脫羧酶在不依賴泛素之下被蛋白酶體降解。全長具功能性的抑酶之生成主要是受到細胞內多胺濃度的調控，而且必需要經過核醣核酸讀碼框+1位移的過程。然而，直至目前為止，抑酶在細胞內詳細的生理功能仍是未明。當哺乳類細胞受到外來刺激如雙股RNAs或是病毒感染時會誘發干擾素的生成。此外在大多數病毒感染下，T細胞在免疫反應中會被誘發導致活化及分化並且產生不同的細胞激素以抵禦病毒感染。文獻報告干擾素具有抗病毒與抗細胞生長之能力部分是藉由2''-5''寡腺苷-RNase L RNA降解路徑。近年來，這條路徑已被證實會增加轉譯過程跳讀過premature終止密碼之效率以及在抑酶轉譯過程中讀碼框+1位移區域之+1位移效率增加。為了探討全長具功能性的抑酶在T細胞活化過程中所扮演的角色，本論文研究抑酶的過度表現對於Jurkat T細胞活化指標特性的影響。利用四環素誘導系統誘發Jurkat T細胞內轉殖的抑酶基因表現，觀察發現抑酶的過度表現會影響許多細胞激素的表現，特別是與免疫活化相關的細胞激素，包括介白素-2、介白素-4、介白素-5、介白素-12 p40及干擾素-γ。其中介白素-2在Jurkat T細胞活化過程中扮演著一個中心細胞激素的角色。研究結果發現抑酶過表現所引發的介白素-2基因的表現可能是透過轉錄層次的調控。進一步分析已知的活化訊息傳遞路徑，發現抑酶誘發後及T細胞活化短時間內，IKKα/β及IκB-α磷酸化表現是增加的，而IκB-α整體蛋白質表現量則有明顯的減少，且下游的NF-κB在活化後進入細胞核的程度也是增加的。總結以上的實驗結果，本論文提出全長具功能性的抑酶具有免疫調控的能力，且進一步影響介白素-2的表現進而去調節T淋巴細胞監督及活化等功能。
Antizyme (AZ) directly binds ornithine decarboxylase (ODC), the key enzyme in polyamine biosynthesis, and inactivates and degrades ODC by the 26S proteasome without ubiquitination. The production of full-length functional AZ protein depends on polyamine levels and AZ gene requires +1 translational frameshifting. However, the delicately cellular function of AZ is still unidentified. Mammalian cells in response to various stimuli such as double-stranded RNAs or viral infection can stimulate the induction of interferons (IFNs). In most viral infections, T cells can be induced to activate, differentiate and produce a number of cytokines that defend against viruses. Previous studies have shown the antiviral and antiproliferative effects of IFNs are mediated by the 2’-5’oligoadenylate RNase L RNA decay pathway. Recently, this pathway is confirmed to increase translational readthrough efficiency at premature termination codons and increase +1 frameshift efficiency at the AZ +1 frameshift site. To elucidate the role of full-length functional AZ in T cell activation, we examined whether conditional expression of full-length AZ protein could elucidate the hallmarks of Jurkat T cell activation. Using Jurkat Tet-On System, AZ overexpression was found to affect the expression of cytokines, especially the cytokines of immuno-activation, including IL-2, IL-4, IL-5, IL-12 (p40) and IFN-γ. The specific activation of IL-2 is a pivotal cytokine in Jurkat T cell activation. This study demonstrated that AZ-triggered expression of IL-2 might be through the transcriptional modulation of IL-2 gene. Further analysis on the signaling transduction revealed that phosphorylation of IKKα/β and IκB-α were increased, total IκB-α was degraded and the nuclear translocation of NF-κB was moderately increased at early stage of activation after AZ induction. Taken together, we suggest that AZ may own the capacity of immuno-regulation and influence IL-2 expression to regulate T lymphocyte surveillance and activation.
