本期文章：《科学》：Volume 382 Issue 6668

美国斯坦福大学Carolyn R. Bertozzi等研究人员合作发现，通过溶酶体靶向嵌合体阐明靶向膜蛋白降解的细胞决定因素。相关论文于2023年10月20日发表在《科学》杂志上。

研究人员表示，在开发治疗策略时，靶向蛋白质降解比抑制方法更具优势。溶酶体靶向嵌合体（LYTAC）利用阳离子非依赖的6-磷酸甘露糖受体（CI-M6PR）等受体将细胞外蛋白引导至溶酶体。

研究人员采用了一种全基因组的CRISPR基因敲除方法，以确定人体细胞中LYTAC介导的膜蛋白降解的调节因子。研究人员发现，破坏retromer基因可减少LYTAC向质膜的再循环，从而改善靶标降解。修饰的cullin-3促进了LYTAC复合物溶酶体的成熟，是LYTAC疗效的预测标志物。细胞表面CI-M6PR的很大一部分仍被内源性M6P修饰的糖蛋白占据。因此，抑制M6P的生物合成会增加LYTAC目标复合物的内化。这些研究结果为下一代LYTAC的设计策略提供了参考，并阐明了细胞表面受体占据和贩运的各个方面。

附：英文原文

Title: Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras

Author: Green Ahn, Nicholas M. Riley, Roarke A. Kamber, Simon Wisnovsky, Salvador Moncayo von Hase, Michael C. Bassik, Steven M. Banik, Carolyn R. Bertozzi

Issue&Volume: 2023-10-20

Abstract: Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6–phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells. We found that disrupting retromer genes improved target degradation by reducing LYTAC recycling to the plasma membrane. Neddylated cullin-3 facilitated LYTAC-complex lysosomal maturation and was a predictive marker for LYTAC efficacy. A substantial fraction of cell surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Thus, inhibition of M6P biosynthesis increased the internalization of LYTAC-target complexes. Our findings inform design strategies for next-generation LYTACs and elucidate aspects of cell surface receptor occupancy and trafficking.

DOI: adf6249