The tumor suppressor Fhit in complex with the alarmone Ap3A binds to the ribosome and impedes translation

Upon cellular stress, the concentration of the alarmone diadenosine triphosphate (Ap3A) increases and is thought to trigger downstream adaptive processes. The known Ap3A-hydrolase fragile histidine triad (Fhit) is known to form a complex with Ap3A. The molecular mechanism of Fhit-Ap3A signaling is however unknown. In this study, by synthesizing a covalent Fhit-Ap3A complex we have elucidated the Ap3A-dependent cellular interactome by mass spectrometry-based proteome profiling. Interestingly, we found a significant enrichment of proteins involved in translation. We then show that Fhit translocates from the nucleolus into the cytosol upon stress to form a Fhit-Ap3A complex which impedes translation both in vitro and in vivo in an Ap3A dependent manner resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap3A to regulate cellular proliferation.

当细胞发生应激时，报警素二腺苷三磷酸（diadenosine triphosphate, Ap3A）的浓度会升高，且被认为会触发下游适应性过程。目前已知的Ap3A水解酶脆性组氨酸三联体（fragile histidine triad, Fhit）可与Ap3A形成复合物，但Fhit-Ap3A信号通路的分子机制仍不明确。本研究通过合成共价Fhit-Ap3A复合物，借助基于质谱的蛋白质组学分析阐明了Ap3A依赖的细胞相互作用组。有趣的是，我们发现与翻译过程相关的蛋白质出现了显著富集。随后我们证实，应激状态下Fhit会从核仁转移至细胞质基质，形成Fhit-Ap3A复合物，该复合物可通过Ap3A依赖的方式在体外和体内抑制翻译过程，最终导致细胞存活率降低。综上，我们的研究结果提出了一套机制模型：肿瘤抑制因子Fhit可与报警素Ap3A协同调控细胞增殖。