在O-GlcNAcylation稳定下,WTAP以N6-甲基氨酸依赖的方式促进GBM恶性进展
Jiawei Qiu1,2, Rongrong Zhao1,2, Caizhi Ma1,2
1Shandong Key Laboratory of Brain Health and Functional Remodeling, Jinan, Shandong, China.
Neuro-oncology
|December 13, 2024
概括
威尔姆斯威尔姆斯是什么意思
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 介细胞性质母细胞 (MES GSCs) 和髓质母细胞衍生的巨细胞 (MDMs) 创造了一个瘤免疫抑制微环境 (TIME),驱动质母细胞 (GBM) 的进展.
- N6-甲基氨酸 (m6A) 修饰与瘤进展有关,但其在塑造GBM TIME中的作用尚不清楚.
研究的目的:
- 调查在GBM时间内MES GSCs和MDMs之间调节相互作用的m6A修饰的机制.
- 确定参与m6A介导的GBM进展和免疫逃避调节的关键分子参与者.
主要方法:
- 利用单细胞和大量RNA测序来确定WTAP在MES GSC-MDM相互作用中的作用.
- 采用了体外和体内模型来确认WTAP的生物功能.
- 进行了质谱,RNA免疫沉降 (RIP) 和共免疫沉降试验,以阐明分子机制.
主要成果:
- 确定了WTAP作为一个关键的m6A甲基转移酶,由OGT和USP7稳定,促进LOXL2mRNA稳定和分泌 (sLOXL2).
- 发现sLOXL2通过整合蛋白α5β1激活了GSC (自身蛋白) 和MDM (副蛋白) 中的FAK-ERK信号,促进了GSC介质细胞过渡和M2型MDM极化.
- 证明sLOXL2诱导的MDM变化有助于T细胞疲劳和GBM免疫逃逸.
- 显示OGT抑制和LOXL2抗的结合在转化模型中改善了抗PD1免疫疗法的结果.
结论:
- 在GBM中,WTAP对于GSC介质细胞过渡和TIME形成至关重要.
- 针对WTAP及其下游效应物,如LOXL2,代表了一种有希望的治疗策略,以提高GBM免疫疗法的疗效.
相关概念视频
Oligosaccharide Assembly
2.8K
Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
Multiple sugar molecules that may or may...
2.8K
mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K
RNA Editing
8.9K
RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the...
8.9K
PI3K/mTOR/AKT Signaling Pathway
3.4K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.4K
Abnormal Proliferation
4.4K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
Protein Glycosylation
6.8K
Glycosylation, the most common post-translational modification for proteins, serves diverse functions. Adding sugars to proteins makes the proteins more resistant to proteolytic digestion. Glycosylated proteins can act as markers and receptors to promote cell-cell adhesion. Additionally, they have many essential quality control functions in the cell, such as correct protein folding and facilitating transport of misfolded proteins to the cytosol, which can be degraded.
Glycosylation occurs in...
Glycosylation occurs in...
6.8K


