當細胞中鋅離子含量過高，或細胞遭受重金屬的毒性、氧化壓力、缺氧等逆境時，會透過活化金屬感應轉錄因子(MTF-1)，使得MTF-1轉錄活化下游基因，例如金屬硫蛋白大量表現，幫助細胞調節鋅離子恆定，或是對抗重金屬毒性以及氧化逆境。經由Mtf-1基因剃除實驗發現MTF-1是小鼠胚胎發育過程中的必要因子。我們的研究發現MTF-1會被進行sumoylation轉譯後修飾作用，並且藉由定點突變的實驗，我們確認此SUMO共價鍵結的作用位置是發生在MTF-1蛋白C端區域的Lys627殘基上，而此SUMO結合位置Lys627在許多物種的MTF-1都是具有保留性的。我們將SUMO-1蛋白融合至MTF-1的C端區域用以模擬MTF-1被進行SUMO修飾作用，結果顯示MTF-1-SUMO融合蛋白的轉錄活性顯著地受到抑制。然而，sumoylation造成的轉錄活性抑制現象，並不是透過影響MTF-1受金屬鋅刺激後移動進入細胞核的能力，也不是改變MTF-1與下游基因結合的能力，甚至也不影響MTF-1蛋白質的穩定性。我們進一步觀察發現鋅刺激會導致MTF-1的SUMO修飾程度降低，此SUMO修飾程度下降的現象和金屬濃度以及處理時間有相關；然而這樣的現象使得sumoylation對於抑制MTF-1轉錄活性的生理意義變的薄弱，因為當鋅刺激後MTF-1會進入細胞核，並且此時sumoylation修飾作用消失。
我們也進一步發現，在SUMO修飾作用位置的前端是一段具有功能的SUMO-interacting motif (SIM)序列。此段SIM序列並不參與調控MTF-1自身受sumoylation修飾作用；但是當SIM序列被破壞時，會導致MTF-1的轉錄活性降低，顯示此段SIM序列對於維持MTF-1轉錄活性是必要的。更值得注意的是，MTF-1透過SIM和被SUMO修飾的MTF-1分子交互結合，並且經由凝膠過濾層析實驗，我們確認MTF-1單體藉由SIM序列和其他MTF-1分子以及細胞內其他蛋白質形成複合體。而此MTF-1的交互作用是發生在細胞質，當細胞遭受金屬刺激時，MTF-1移動進入細胞核中，此時MTF-1複合體便瓦解，並且細胞核的環境使得已解開的MTF-1無法再結合成高分子量的複合體。因此我們歸納出MTF-1的sumoylation修飾作用以及SIM序列對於抑制MTF-1轉錄活性方面並不扮演關鍵性的角色；重要的是，MTF-1會藉由SIM序列和SUMO的結合而在細胞質中形成複合體。
透過本篇的研究成果，我們首次發現MTF-1會被進行sumoylation修飾作用，並且會以複合體的形式存在於細胞質中。我們在此提出一個新的模式來說明MTF-1需要透過SIM序列與SUMO作用才得以組合成複合體，此MTF-1複合體的存在是會受金屬調控。

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Metal-responsive transcription factor 1 (MTF-1) is an essential protein required for mouse embryonic development. We report here the occurrence of sumoylation on MTF-1. Mutational studies demonstrated that sumoylation occurs on the lysine residue at position 627 (Lys627) of mouse MTF-1. Small ubiquitin-like modifier (SUMO)-1 was fused to the C terminus of MTF-1 to mimic the sumoylated form of the protein and it suppressed the transcriptional activity of MTF-1. The nuclear translocation activity, DNA-binding activity, and protein stability of SUMO-fused MTF-1 are similar to that of wild type MTF-1. The level of sumoylation was reduced by metal in a dose- and time-dependent manner. The fact that zinc reduces MTF-1 sumoylation makes the suppressive role of sumoylated MTF-1 in transcription physiologically less significant because the SUMO moiety of MTF-1 is removed when MTF-1 translocates into the nucleus.
We further identified a SUMO-interacting motif (SIM) on MTF-1. Remarkably, MTF-1 binds sumoylated MTF-1 and/or other cellular factors in a SIM-dependent manner. This interaction was disrupted by treating cells with zinc. Gel permeation chromatography demonstrated that MTF-1 forms SIM-dependent complexes. This cross-interaction transpires in the cytoplasm and markedly reduces upon nuclear translocation. It can therefore be concluded that SUMO conjugation and the SIM on MTF-1 do not play a critical role in suppressing transcriptional activity. Instead, MTF-1 forms complexes with cellular factors through SIM and SUMO moiety in the cytoplasm. The result explores a new understanding for the mode of MTF-1 assembly and regulation in cells.

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