Kalasa Anil Kumar Apoorva Pai, Subair Suhail, Basthikoppa Shivamurthy Prathik, Ummar Samseera, Rajeev Athira C, Raju Rajesh
Yenepoya University, Mangalore, India.
Protein J. 2025 Aug 30. doi: 10.1007/s10930-025-10287-4.
Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2's intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.
ataxin-2（ATXN2）是一种关键的RNA结合蛋白，可调节RNA代谢、应激颗粒形成和神经元稳态，磷酸化失调会导致2型脊髓小脑共济失调（SCA2）、肌萎缩侧索硬化症（ALS）和癌症。本综述整合了结构生物学、磷酸化蛋白质组学和相互作用组分析，以绘制ATXN2内在无序区域内的六个关键磷酸化位点（S772、T741、S624、S684、S784、S889）。这些位点受激酶GSK3β和CDK13以及诸如INPP5F等磷酸酶的调节，协调与RNA结合伙伴（如ATXN2L、FXR2、STAU2）和共同调节蛋白（如TP53BP1、NUP153）的相互作用，通过破坏自噬、核质运输和应激颗粒动力学来驱动发病机制。我们提出了靶向治疗方法，包括用于ALS的GSK3β抑制剂、用于SCA2的反义寡核苷酸和用于癌症的mTOR调节剂，以恢复ATXN2功能。通过阐明ATXN2的磷酸化密码，这项工作突出了神经退行性疾病和致癌疾病精准医学的新途径。
