Department of Biological Sciences, Pusan National University, Busan, Republic of Korea.
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
Exp Mol Med. 2018 Jan 26;50(1):e434. doi: 10.1038/emm.2017.247.
An interaction between ribosomal protein S3 (rpS3) and nuclear factor kappa B or macrophage migration inhibitory factor in non-small-cell lung cancer is responsible for radioresistance. However, the role of rpS3 in glioblastoma (GBM) has not been investigated to date. Here we found that in irradiated GBM cells, rpS3 translocated into the nucleus and was subsequently ubiquitinated by ring finger protein 138 (RNF138). Ubiquitin-dependent degradation of rpS3 consequently led to radioresistance in GBM cells. To elucidate the apoptotic role of rpS3, we analyzed the interactome of rpS3 in ΔRNF138 GBM cells. Nuclear rpS3 interacted with DNA damage inducible transcript 3 (DDIT3), leading to DDIT3-induced apoptosis in irradiated ΔRNF138 GBM cells. These results were confirmed using in vivo orthotopic xenograft models and GBM patient tissues. This study aims to clarify the role of RNF138 in GBM cells and demonstrate that rpS3 may be a promising substrate of RNF138 for the induction of GBM radioresistance, indicating RNF138 as a potential target for GBM therapy.
核糖体蛋白 S3（rpS3）与核因子 kappa B 或巨噬细胞移动抑制因子在非小细胞肺癌中的相互作用是其产生放射抗性的原因。然而，目前尚未研究 rpS3 在胶质母细胞瘤（GBM）中的作用。在这里，我们发现，在辐照的 GBM 细胞中，rpS3 易位到细胞核中，并随后被环指蛋白 138（RNF138）泛素化。rpS3 的泛素依赖性降解导致 GBM 细胞产生放射抗性。为了阐明 rpS3 的凋亡作用，我们分析了 ΔRNF138 GBM 细胞中 rpS3 的相互作用组。核 rpS3 与 DNA 损伤诱导转录物 3（DDIT3）相互作用，导致辐照的 ΔRNF138 GBM 细胞中 DDIT3 诱导的细胞凋亡。这些结果在体内原位异种移植模型和 GBM 患者组织中得到了验证。本研究旨在阐明 RNF138 在 GBM 细胞中的作用，并证明 rpS3 可能是 RNF138 诱导 GBM 放射抗性的有前途的底物，表明 RNF138 是 GBM 治疗的潜在靶点。
