Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Cell. 2013 Feb 28;152(5):1134-45. doi: 10.1016/j.cell.2013.02.003.
Translocation into the endoplasmic reticulum (ER) is an initial and crucial biogenesis step for all secreted and endomembrane proteins in eukaryotes. ER insertion can take place through the well-characterized signal recognition particle (SRP)-dependent pathway or the less-studied route of SRP-independent translocation. To better understand the prevalence of the SRP-independent pathway, we systematically defined the translocational dependence of the yeast secretome. By combining hydropathy-based analysis and microscopy, we uncovered that a previously unappreciated fraction of the yeast secretome translocates without the aid of the SRP. Furthermore, we validated a family of SRP-independent substrates-the glycosylphosphatidylinositol (GPI)-anchored proteins. Studying this family, we identified a determinant for ER targeting and uncovered a network of cytosolic proteins that facilitate SRP-independent targeting and translocation. These findings highlight the underappreciated complexity of SRP-independent translocation, which enables this pathway to efficiently cope with its extensive substrate flux.
易位子进入内质网（ER）是真核生物所有分泌蛋白和内膜蛋白生物发生的初始和关键步骤。ER 插入可以通过特征明确的信号识别颗粒（SRP）依赖性途径或研究较少的 SRP 非依赖性易位途径进行。为了更好地理解 SRP 非依赖性途径的普遍性，我们系统地定义了酵母分泌组的易位依赖性。通过结合疏水性分析和显微镜，我们发现酵母分泌组的一个以前未被重视的部分在没有 SRP 的帮助下进行易位。此外，我们验证了一组 SRP 非依赖性底物——糖基磷脂酰肌醇（GPI）锚定蛋白。研究这个家族，我们确定了 ER 靶向的决定因素，并发现了一个促进 SRP 非依赖性靶向和易位的细胞质蛋白网络。这些发现强调了 SRP 非依赖性易位的被低估的复杂性，这使得该途径能够有效地应对其广泛的底物通量。
