Zhang Yumeng, Ogata Yoshiyasu, Nadanaka Satomi, Kitagawa Hiroshi, Era Takumi, Matsuo Muneaki
Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
Laboratory of Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
FASEB J. 2025 Aug 15;39(15):e70909. doi: 10.1096/fj.202500742R.
RAD50-interacting protein1 (RINT1) deficiency has been implicated in recurrent acute liver failure (RALF) triggered by fever or infections. RINT1, together with neuroblastoma amplified sequence and Zeste White 10 (forming the NRZ complex), localizes at the interface between the endoplasmic reticulum and Golgi apparatus, where it plays a key role in vesicular trafficking. However, the mechanisms by which RINT1 deficiency leads to RALF remain unclear. This study aimed to describe a woman with RALF harboring a homozygous missense mutation in RINT1. Induced pluripotent stem cells (iPSCs) were generated from the patient's mononuclear cells and differentiated into hepatocyte-like cells (HLCs). Upon exposure to high temperature (40°C), RINT1-deficient HLCs exhibited cellular damage characteristic of RALF. Furthermore, these cells also demonstrated heightened sensitivity to cytokines and viral mimetics while showing comparatively lower responsiveness to bacterial infection-related stimuli. Transcriptome sequencing revealed dysregulated gene expression associated with the extracellular matrix (ECM). Additionally, glycosaminoglycan disaccharide analysis revealed abnormal levels of chondroitin sulfate, heparan sulfate, and hyaluronan in RINT1-deficient HLCs. In conclusion, HLCs derived from RINT1-deficient iPSCs serve as a valuable model for investigating RINT1-related liver pathogenesis. The results suggest that cytokine responses, particularly those triggered by viral infections, play a central role in the development of RALF. Furthermore, ECM alterations provided novel insights into the potential role of RINT1 defects in RALF.
RAD50相互作用蛋白1（RINT1）缺陷与发热或感染引发的复发性急性肝衰竭（RALF）有关。RINT1与神经母细胞瘤扩增序列和Zeste White 10（形成NRZ复合物）一起定位于内质网和高尔基体之间的界面，在囊泡运输中起关键作用。然而，RINT1缺陷导致RALF的机制仍不清楚。本研究旨在描述一名患有RALF且RINT1存在纯合错义突变的女性。从患者的单核细胞中生成诱导多能干细胞（iPSC），并将其分化为肝细胞样细胞（HLC）。在暴露于高温（40°C）时，RINT1缺陷的HLC表现出RALF特征性的细胞损伤。此外，这些细胞对细胞因子和病毒模拟物也表现出更高的敏感性，而对细菌感染相关刺激的反应相对较低。转录组测序揭示了与细胞外基质（ECM）相关的基因表达失调。此外，糖胺聚糖二糖分析显示RINT1缺陷的HLC中硫酸软骨素、硫酸乙酰肝素和透明质酸水平异常。总之，源自RINT1缺陷iPSC的HLC是研究RINT1相关肝脏发病机制的宝贵模型。结果表明，细胞因子反应，特别是由病毒感染触发的反应，在RALF的发展中起核心作用。此外，ECM改变为RINT1缺陷在RALF中的潜在作用提供了新的见解。
