Targeted protein relocalization via protein transport coupling

• 成果类型: Article
• 署名作者: Ng, Christine S. C.; Liu, Aofei; Cui, Bianxiao; Banik, Steven M.
• 署名单位: Stanford University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6806
• DOI: 10.1038/s41586-024-07950-8
• 发表日期: 2024-09-26
• 页码: 941-+
• 关键词: nuclear export; nucleocytoplasmic transport; axonal protection; wld(s); cancer; localization; fus; degeneration; mutations; location

摘要

Subcellular protein localization regulates protein function and can be corrupted in cancers(1) and neurodegenerative diseases(2,3). The rewiring of localization to address disease-driving phenotypes would be an attractive targeted therapeutic approach. Molecules that harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could enforce targeted protein relocalization and rewire the interactome. Here we identify a collection of shuttle proteins with potent ligands amenable to incorporation into targeted relocalization-activating molecules (TRAMs), and use these to relocalize endogenous proteins. Using a custom imaging analysis pipeline, we show that protein steady-state localization can be modulated through molecular coupling to shuttle proteins containing sufficiently strong localization sequences and expressed in the necessary abundance. We analyse the TRAM-induced relocalization of different proteins and then use nuclear hormone receptors as shuttles to redistribute disease-driving mutant proteins such as SMARCB1(Q318X), TDP43(Delta NLS) and FUSR495X. TRAM-mediated relocalization of FUSR495X to the nucleus from the cytoplasm correlated with a reduction in the number of stress granules in a model of cellular stress. With methionyl aminopeptidase 2 and poly(ADP-ribose) polymerase 1 as endogenous cytoplasmic and nuclear shuttles, respectively, we demonstrate relocalization of endogenous PRMT9, SOS1 and FKBP12. Small-molecule-mediated redistribution of nicotinamide nucleotide adenylyltransferase 1 from nuclei to axons in primary neurons was able to slow axonal degeneration and pharmacologically mimic the genetic WldS gain-of-function phenotype in mice resistant to certain types of neurodegeneration(4). The concept of targeted protein relocalization could therefore inspire approaches for treating disease through interactome rewiring.