Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada H1T 2M4.
Biochem Biophys Res Commun. 2013 Mar 29;433(1):90-5. doi: 10.1016/j.bbrc.2013.02.059. Epub 2013 Feb 26.
Sortilin is a transmembrane domain protein that has been implicated in the sorting of prosaposin and other soluble cargo from the Golgi to the lysosomal compartment. While the majority of the receptor is recycled back to the Golgi from endosomes, it is known that upon successive rounds of transport, a proportion of sortilin is degraded in lysosomes. Recently, it was shown that sortilin is palmitoylated and that this post-translational modification prevents its degradation and enables sortilin to efficiently traffic back to the Golgi. Thus palmitoylation can be used to modulate the amount of receptor and hence cargo reaching the lysosome. In this work, we demonstrate that non-palmitoylated sortilin is ubiquitinated and internalized into the lysosomal compartment via the ESCRT pathway for degradation. Furthermore, we identified Nedd4 as an E3 ubiquitin ligase that mediates this post-translational modification. We propose a model where palmitoylation and ubiquitination play opposite roles in the stability and turnover of sortilin and serve as a control mechanism that balances the amount of lysosomal sorting and trafficking in cells.
Sortilin 是一种跨膜域蛋白，它与前导序列素和其他可溶性货物从高尔基体到溶酶体隔室的分拣有关。虽然大部分受体从内体循环回高尔基体，但已知在连续的运输轮次中，一部分 Sortilin 在溶酶体中降解。最近，已经表明 Sortilin 是棕榈酰化的，这种翻译后修饰可以防止其降解，并使 Sortilin 能够有效地返回高尔基体。因此，棕榈酰化可以用来调节到达溶酶体的受体和货物的数量。在这项工作中，我们证明了非棕榈酰化的 Sortilin 是通过 ESCRT 途径泛素化和内化到溶酶体隔室中进行降解的。此外，我们确定了 Nedd4 是一种 E3 泛素连接酶，介导这种翻译后修饰。我们提出了一个模型，其中棕榈酰化和泛素化在 Sortilin 的稳定性和周转率中起着相反的作用，并作为一种控制机制，平衡细胞中溶酶体分拣和运输的数量。
