School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
Curr Top Microbiol Immunol. 2012;357:19-40. doi: 10.1007/82_2011_154.
A number of protein toxins bind at the surface of mammalian cells and after endocytosis traffic to the endoplasmic reticulum, where the toxic A chains are liberated from the holotoxin. The free A chains are then dislocated, or retrotranslocated, across the ER membrane into the cytosol. Here, in contrast to ER substrates destined for proteasomal destruction, they undergo folding to a catalytic conformation and subsequently inactivate their cytosolic targets. These toxins therefore provide toxic probes for testing the molecular requirements for retrograde trafficking, the ER processes that prepare the toxic A chains for transmembrane transport, the dislocation step itself and for the post-dislocation folding that results in catalytic activity. We describe here the dislocation of ricin A chain and Shiga toxin A chain, but also consider cholera toxin which bears a superficial structural resemblance to Shiga toxin. Recent studies not only describe how these proteins breach the ER membrane, but also reveal aspects of a fundamental cell biological process, that of ER-cytosol dislocation.
许多蛋白毒素与哺乳动物细胞表面结合，然后通过内吞作用运输到内质网，在那里，毒素的 A 链从完整毒素中释放出来。然后，游离的 A 链穿过内质网膜进入细胞质，发生移位或逆行转运。与内质网中注定要被蛋白酶体破坏的底物不同，它们在细胞质中折叠成催化构象，随后失活其细胞质靶标。因此，这些毒素为测试逆行运输的分子要求、为跨膜运输准备毒性 A 链的内质网过程、易位步骤本身以及导致催化活性的易位后折叠提供了有毒探针。我们在这里描述了蓖麻毒素 A 链和志贺毒素 A 链的易位，但也考虑了霍乱毒素，它与志贺毒素具有表面结构上的相似性。最近的研究不仅描述了这些蛋白质如何突破内质网膜，还揭示了内质网-细胞质易位这一基本细胞生物学过程的各个方面。
