Unphosphorylated tyrosines mediate PD-1 inhibition of T cell signaling condensate formation

• 成果类型: Article
• 署名作者: Sharma, Monica; Katz, Zachary B.; Dewitt, David C.; Ruff, Kiersten M.; Singh, Akashdip; Lan, Huan; Phung, Wilson; Tom, Jeffery; Song, Aimin; Sudhamsu, Jawahar; Davies, John; Quinn, John G.; Pappu, Rohit V.; Shaw, Andrey S.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adt9365
• 发表日期: 2026-09-10
• 页码: 1145-1151
• 关键词: SURFACE-PLASMON RESONANCE; phase-separation; receptor; activation; complexes; antigen; transduction; checkpoint; protein; LINKER

摘要

T cell receptor (TCR) engagement stimulates formation of a biomolecular condensate, including the scaffold protein linker of activated T cells (LAT). We investigated whether the immune-inhibitory receptor programmed cell death protein 1 (PD-1) inhibits by impeding TCR-induced LAT condensation. In vitro reconstitutions revealed that the cytoplasmic domain of PD-1 directly inhibited LAT condensation. This inhibitory interaction required tyrosine residues in the two inhibitory motifs of PD-1. Contrary to current working models, tyrosine phosphorylation eliminated PD-1 inhibition. Replacing tyrosine with tryptophan reconstituted PD-1 inhibition in T cells, confirming that phosphorylation does not mediate this effect. These findings support the concept that hydrogen bond-donating aromatic residues within inhibitory motifs provide the primary mechanism that explains how inhibitory receptors disrupt signaling networks and block immune activation.