Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62.
Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62.
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DOI：
10.1016/j.bbrc.2021.01.023
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发表时间：
2021-01
影响因子：
3.1
通讯作者：
E. Aonuma;Akiko Tamura;Hiroki Matsuda;Takehito Asakawa;Y. Sakamaki;Kana Otsubo;Yoichi Nibe;Michio Onizawa;Y. Nemoto;T. Nagaishi;K. Tsuchiya;Tetsuya Nakamura;M. Uo;Mamoru Watanabe;R. Okamoto;S. Oshima
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文献类型：
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作者：
E. Aonuma;Akiko Tamura;Hiroki Matsuda;Takehito Asakawa;Y. Sakamaki;Kana Otsubo;Yoichi Nibe;Michio Onizawa;Y. Nemoto;T. Nagaishi;K. Tsuchiya;Tetsuya Nakamura;M. Uo;Mamoru Watanabe;R. Okamoto;S. Oshima
镍是最常见的接触性过敏物质，被广泛用于各种金属材料和医疗器械。自噬是一种细胞内蛋白质降解系统，有助于金属的再循环。然而，镍在自噬中的作用尚不清楚。我们在这里证明了NiCl2诱导微管相关蛋白1轻链3 (LC3)-II和LC3点，自噬体的标志物。在NiCl2刺激下，巴菲霉素A1 （BafA1）处理没有增强LC3点，提示NiCl2没有诱导自噬通量。此外，NiCl2促进SQSTM1/p62的积累，并增加SQSTM1/p62与溶酶体相关膜蛋白1 （LAMP1）的共定位。这些数据表明，NiCl2可以减弱自噬通量。有趣的是，NiCl2诱导高分子量（MW）形式的SQSTM1/p62的表达。抑制nicl2诱导的活性氧（ROS）可降低高分子量的SQSTM1/p62。我们还发现nicl2诱导的ROS激活了谷氨酰胺转胺酶（TG）的活性。我们发现，在NiCl2刺激下，转谷氨酰胺酶2 （TG2）抑制降低了高分子量SQSTM1/p62和SQSTM1/p62点，表明TG2在NiCl2刺激下调节SQSTM1/p62蛋白稳态。我们的研究表明，镍离子调节自噬通量，TG2限制镍依赖的蛋白质稳态。
Nickel, the most frequent contact allergy cause, is widely used for various metallic materials and medical devices. Autophagy is an intracellular protein degradation system and contributes to metal recycling. However, it is unclear the functions of nickel in autophagy. We here demonstrated that NiCl2 induced microtubule-associated protein 1 light chain 3 (LC3)-II and LC3 puncta, markers of autophagosomes. Bafilomycin A1 (BafA1) treatment did not enhance LC3 puncta under NiCl2 stimulation, suggesting that NiCl2 did not induce autophagic flux. In addition, NiCl2 promotes the accumulation of SQSTM1/p62 and increased SQSTM1/p62 colocalization with lysosomal-associated membrane protein 1 (LAMP1). These data indicated that NiCl2 attenuates autophagic flux. Interestingly, NiCl2 induced the expression of the high-molecular-weight (MW) form of SQSTM1/p62. Inhibition of NiCl2-induced reactive oxygen species (ROS) reduced the high-MW SQSTM1/p62. We also showed that NiCl2-induced ROS activate transglutaminase (TG) activity. We found that transglutaminase 2 (TG2) inhibition reduced high-MW SQSTM1/p62 and SQSTM1/p62 puncta under NiCl2 stimulation, indicating that TG2 regulates SQSTM1/p62 protein homeostasis under NiCl2 stimulation. Our study demonstrated that nickel ion regulates autophagy flux and TG2 restricted nickel-dependent proteostasis.