Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0379 Oslo, Norway.
Department of Biosciences, University of Oslo, 0315 Oslo, Norway.
Toxins (Basel). 2022 May 22;14(5):360. doi: 10.3390/toxins14050360.
The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed.
化合物 EACC（乙基（2-（5-硝基噻吩-2-甲酰胺基）噻吩-3-羰基）氨基甲酸酯）最近被报道通过抑制衔接蛋白 17 向自噬体的募集，以可逆的方式抑制自噬体与溶酶体的融合。我们在这里报告，该化合物还能强烈抵抗蛋白毒素蓖麻毒素以及其他植物毒素，如相思豆毒素和 Modeccin。这种保护似乎不是由于抑制内吞作用和逆行运输引起的，而是由于抑制了酶活性 A 部分向细胞质的释放。TANK 结合激酶 1（TBK1）已被报道能磷酸化衔接蛋白 17，并被认为是自噬起始所必需的。TBK1 的抑制剂 MRT68601 本身会引起对蓖麻毒素的强烈敏化作用，显然是通过增加向高尔基体的运输。重要的是，即使在存在 EACC 的情况下，MRT68601 仍能促进蓖麻毒素的高尔基体运输，但 EACC 仍能抑制中毒，这支持了 EACC 在逆行途径的晚期起保护作用的观点。这些结果还表明，观察到的保护作用不需要衔接蛋白 17 的磷酸化。
