GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling

• 成果类型: Article
• 署名作者: Zhou, Changqian; Zhang, Miao; Murray, Jason; Paulo, Joao; Gygi, Steve; Shao, Sichen; Whitman, Malcolm; Keller, Tracy
• 署名单位: Harvard University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ads8728
• 发表日期: 2025-10-02
• 页码: eads8728
• 关键词: unfolded protein response; decoy search strategy; TRANSFER-RNA-BINDING; KINASE GCN2; mass-spectrometry; structural basis; saccharomyces-cerevisiae; TRANSLATION SYSTEM; EIF2-ALPHA KINASE; quality-control

摘要

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.