Abstract:
Extracellular proteins with important signalling roles in processes, such as inflammation and angiogenesis, are known to employ unconventional routes of protein secretion. Although mechanisms of unconventional protein secretion are beginning to emerge, the precise molecular details have remained elusive for the majority of cargo proteins secreted by unconventional means. Recent findings suggest that for two examples of unconventionally secreted proteins, interleukin 1β (IL-1β) and fibroblast growth factor 2 (FGF2), the common molecular principle of pore formation may be shared. Under specific experimental conditions, secretion of IL-1β and FGF2 is triggered by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]-dependent formation of pores across the plasma membrane. However, the underlying mechanisms are different, with FGF2 known to directly interact with PI(4,5)P2, whereas in the case of IL-1β secretion, it is proposed that the N-terminal fragment of gasdermin D interacts with PI(4,5)P2 to form the pore. Thus, although implemented in different ways, these findings suggest that pore formation may be shared by the unconventional secretion mechanisms for FGF2 and IL-1β in at least some cases. In this Opinion article, we discuss the unconventional mechanisms of FGF2 and IL-1β release with a particular emphasis on recent discoveries suggesting the importance of pore formation on the plasma membrane.
摘要:
在过程中具有重要信号作用的细胞外蛋白质,比如炎症和血管生成,已知采用非常规的蛋白质分泌途径。尽管非常规蛋白质分泌的机制开始出现,对于通过非常规手段分泌的大多数货物蛋白,精确的分子细节仍然难以捉摸。最近的发现表明,对于两个非常规分泌蛋白的例子,白细胞介素1β(IL-1β)和成纤维细胞生长因子2(FGF2),可以共享孔形成的共同分子原理。在特定的实验条件下,IL-1β和FGF2的分泌由磷脂酰肌醇4,5-二磷酸[PI(4,5)P2]依赖性的跨质膜孔形成触发。然而,潜在的机制是不同的,已知FGF2与PI(4,5)P2直接相互作用,而在IL-1β分泌的情况下,提出gasderminD的N端片段与PI(4,5)P2相互作用形成孔。因此,虽然以不同的方式实施,这些发现表明,至少在某些情况下,FGF2和IL-1β的非常规分泌机制可能共享孔形成。在这篇文章中,我们讨论了FGF2和IL-1β释放的非常规机制,特别强调了最近的发现,表明质膜上孔形成的重要性。