A Glutathione S‑Transferase Pi Molecular Glue Tethers Splicing Factors and Remodels Cell Metabolism

Here, we discovered a tyrosine-reactive GSTP1 inhibitor
can function
as a molecular glue via a ligand induced protein tethering (LIPT)
mechanism. Electrophilic modification of GSTP1 results in disulfide
tethering of protein complexes in live cells, and these protein–protein
interactions (PPIs) can be reversed using reducing agents. A substantial
fraction of GSTP1 tethered interactions represent neo-PPIs that were
enriched for splicing factors and nuclear proteins as determined by
immunopurification mass spectrometry. LIPT colocalized GSTP1 with
serine/arginine repetitive matrix protein 1 (SRRM1), resulting in
its redistribution from nuclear speckles to cytoplasmic foci. Cancer
cells with enhanced sensitivity to LIPT showed downregulation of metabolic
proteins that led to altered lipid metabolism and reduced cell proliferation
from GSTP1 molecular glue treatment. Collectively, we show covalent
molecular glues of GSTP1 can alter localization of disulfide tethered
binding partners and disrupt metabolism in cancer cells.

本研究发现，一款酪氨酸反应性谷胱甘肽S-转移酶π1（GSTP1）抑制剂可通过配体诱导蛋白拴系（LIPT）机制发挥分子胶功能。GSTP1经亲电修饰后，可在活细胞中介导蛋白质复合物的二硫键拴系；此类蛋白质-蛋白质相互作用（PPIs）可通过还原剂逆转。经免疫纯化质谱鉴定，GSTP1介导的拴系相互作用中，有相当比例为新生PPIs，其富集对象为剪接因子与核蛋白。LIPT可将GSTP1与丝氨酸/精氨酸重复基质蛋白1（SRRM1）共定位，促使SRRM1从核斑重新分布至细胞质灶。对LIPT敏感性增强的癌细胞，经GSTP1分子胶处理后，其代谢蛋白表达下调，进而引发脂质代谢异常并抑制细胞增殖。综上，本研究证实，GSTP1的共价分子胶可改变二硫键拴系结合伴侣的亚细胞定位，并破坏癌细胞的代谢过程。