TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.
TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.
复制标题
TRIM65 通过 TPIT 的泛素化和降解来决定垂体神经内分泌肿瘤新亚型的命运。
DOI：
10.1093/neuonc/noac053
复制
发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Shang,Hanb
中科院分区：
文献类型：
--
作者：
Yao,Hong;Xie,Wanqun;Dai,Yuting;Liu,Yanting;Gu,Weiting;Li,Jianfeng;Wu,Liang;Xie,Jing;Rui,Weiwei;Ren,Bohan;Xue,Li;Cheng,Yijun;Lin,Shaojian;Li,Changsheng;Tang,Hao;Wang,Yu;Lou,Meiqing;Zhang,Xiaobiao;Hu,Ronggui;Shang,Hanb
背景垂体神经内分泌肿瘤（PitNETs）是颅内常见的肿瘤，可分为促乳细胞型、促生长细胞型、促肾上腺皮质细胞型、促甲状腺细胞型、促性腺细胞型、空细胞型和多激素型PitNETs。然而，这些类型的PitNETs的分子特征还不完全clear.MethodsA共收集了180例连续的PitNETs进行RNA测序。所有亚型的PitNETs区分无监督聚类分析。我们研究了TRIM65的调节TPIT和其对ACTH分泌垂体细胞系中ACTH的产生和分泌的影响，以及在小鼠模型中使用生化分析，共聚焦显微镜，和荧光素酶报告基因assays.ResultsA新亚型的PitNET来自TPIT谱系细胞被确定为与正常的TPIT转录，但与降低的蛋白质表达。此外，TRIM65首次被鉴定为TPIT的E3泛素连接酶。根据RING结构域，TRIM65在多个Lys位点泛素化并降解TPIT蛋白。此外，TRIM65介导的泛素化的TPIT抑制POMC转录和ACTH的生产，以确定命运的新亚型的PitNETs在体外和invivo.ConclusionOur研究提供了一个新的分类PitNETs，并揭示了TRIM65-TPIT复合物控制的命运的新亚型的PitNETs，这提供了一个潜在的治疗库欣病的目标。
BackgroundPituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear.MethodsA total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays.ResultsA novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETsin vitroandin vivo.ConclusionOur studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing’s disease.