SUMO (Small ubiquitin-like modifier, SUMO) 類泛素蛋白質修飾在多種生物生理功能中扮演重要的角色。蛋白質被SUMO修飾之後，另一類含有SUMO-interacting motif (SIM)的蛋白質會以非共價鍵的方式與SUMO修飾的蛋白質有交互作用。Fas-associated factor 1 (FAF1) 蛋白質為Fas受體的結合蛋白，其功能被證實可以促進Fas所誘導的細胞凋亡。進一步的研究發現FAF1會參與在很多的訊息傳遞路徑以促進細胞死亡和調控泛素化(Ubiquitination)依賴性蛋白質的水解。舉例來說，FAF1蛋白質會透過兩種方式去抑制NF-B的訊息傳遞，第一透過直接與p65蛋白有交互作用，進而抑制p65入核，或者透過抑制I-B kinase (IKK)複合體聚集，進而使I-B水解p65。除此之外，FAF1會促進β-catenin的泛素化及水解以拮抗Wnt路徑。最近研究顯示FAF1對於鹽皮質激素受體(mineralocorticoid receptor , MR)誘導的轉錄活化有differential effects。先前在本實驗室已經發現FAF1含有兩個可能的SIMs。實驗結果發現FAF1 SIMs對於促進Fas誘導的細胞凋亡、抑制NF-B的訊息傳遞及促進β-catenin降解並不扮演重要的角色。然而，我們意外地發現FAF1 SIMs對於FAF1結合到SUMO蛋白質修飾的MR及抑制MR調控的報導基因活性相當的重要。在機制上，我們的結果顯示FAF1會抑制aldosterone誘導MR N-C端的交互作用和轉錄活化，SIMs即扮演重要角色。未來更進一步的研究想去探討在不同荷爾蒙受體上FAF1 SIMs的功能性。我們推測FAF1 SIMs與其他SUMO蛋白質修飾蛋白的交互作用會參與在多種的訊息傳遞路徑中。

Small ubiquitin-like modifier (SUMO) modification plays important roles in the regulation of diverse cellular processes. Notably, SUMO-interacting motif (SIM) is present in proteins mediates noncovalent interactions with a wide variety of SUMO-conjugated proteins. Fas-associated factor 1 (FAF1) was originally identified as a interacting partner of Fas receptor that enhances apoptosis initiated through Fas ligand. Further studies have revealed that FAF1 participates in diverse mechanisms that promote cell death and modulate ubiquitin-dependent protein degradation. For example, FAF1 suppressed NF-B survival pathway by inhibiting I-B kinase (IKK) complex activation or interfering nuclear translocation of the NF-B p65 subunit upon TNFα treatment. Additionally, FAF1 antagonizes canonical Wnt pathway by promoting β-catenin ubiquitination and degradation. Recent studies also demonstrated that differential effects of FAF1 on mineralocorticoid receptor (MR)-driven transactivation. Our laboratory has recently discovered that FAF1 contains two putative SUMO interacting motifs (SIMs). Our previous studies demonstrated that the SIMs of FAF1 are not crucial to promote Fas-induced apoptosis, inhibit NF-B activation, and promote β-catenin degradation. Currently, we found that FAF1 SIMs are required for FAF1 binding to sumoylated MR and repressing MR-mediated reporter activity. Mechanismly, our data showed that FAF1 inhibits aldosterone-induced MR N-C interaction and transactivation in a SIMs-dependent manner. Further studies are required to determine the functional role of FAF1 SIMs in different types of hormone receptors. We speculate that the interactions of FAF1/SIMs with other sumoylated proteins involved in multiple signaling pathways.

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