Retro-2 is a specific retrograde trafficking inhibitor of protein toxins. Retro-2 can selectively block retrograde toxin trafficking at the early endosome-TGN interface and protect cells from ricin and Shiga-like toxins, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, including endocytosis, recycling, degradation, and secretion. Pretreatment with 20μM Retro-2 for 30min could protected HeLa cells from a 4-hour ricin challenge by toxicity reduction of 2.7 fold in HeLa cells, as well as the intoxication by Stx1 and Stx2. Pre-treatment with 20μM Retro-2 inhibited the retrograde transport, but not endocytosis, of STxB to the TGN/Golgi without morphologies of Golgi, ER, of early (EEA1) and recycling endosomes (transferrin receptor [TfR] and Rab11), and of late endosomes/lysosomes (Lamp1) affected. Retro-2 blocked STxB in early endosomes and relocalized Syntaxin 5, but had no effect on endogenous retrograde cargo proteins like CI-MPR and TGN46. Pre-treatment with Retro-2 at dose of 2mg/kg, 10mg/kg, 20mg/kg and 200mg/kg, i.p., for 1h could improve the survival of mice post the ricin toxin challenge in a dose dependent manner[1]. Retro-2 potently prevented spread of vaccinia virus as well as monkeypox virus by preventing wrapping of virions with an additional double-membrane envelope that enables microtubular transport, exocytosis, and actin polymerization[2]. Retro-2 elevated the Aβ42-generating activity, by disruption of endosome-to-TGN trafficking ofγ-secretase, both in cultured cells and mice brain, but did not elevate the intrinsic Aβ42-production activity of γ-secretase[3].
作用机制
Retro-2 could block STxB in early endosomes and specifically inhibit retrograde transport to the trans-golgi network.[1]
搜索
