来自杂志 Molecular cell 的文献。
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1.
LXJ
(2022-09-30 19:06):
#paper DOI:10.1016/j.molcel.2022.01.002. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. mTOR复合物1（mTORC1）是一个重要的代谢中枢，可以将细胞代谢与营养物质（包括氨基酸）的可用性相协调。Sestrin2已被鉴定为一种细胞溶质亮氨酸传感器，可将亮氨酸状态信号传输至mTORC1。在本研究中，作者鉴定了一种E3泛素连接酶环指蛋白167（RNF167）和一种双歧化酶STAMBPL1，二者协同作用，控制Sestrin1的多泛素化水平，以响应亮氨酸的可用性。Sestrin2的泛素化促进其与GATOR2的相互作用并抑制mTORC1信号。生物信息学分析显示胃和结肠肿瘤中RNF167表达降低，STAMBPL1表达增加。在人类结肠癌细胞系中敲除STAMBPL1或纠正杂合STAMBPL 1突变可抑制异种移植瘤的生长。通过上述研究，作者旨在阐述一种阻断STAMBPL1-Sestrin2相互作用的细胞渗透性肽抑制mTORC1，为癌症治疗提供了潜在的选择。
Abstract:
The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine …
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The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy.
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2.
颜林林
(2022-09-16 23:18):
#paper doi:10.1016/j.molcel.2022.08.019 Molecular Cell, 2022, Developmental and housekeeping transcriptional programs in Drosophila require distinct chromatin remodelers. 这篇文章吸引到我，是因为浏览它时，我看到了两个词，“Drosophila（果蝇）”和“auxin（植物生长素）”，于是很好奇这两者是怎么联系起来的。过去在生物专业课上，就听说过植物生长素在植物研究领域中的至尊江湖地位。这篇文章提及一项技术“auxin-inducible degradation (AID)”，源自2009年的一篇Nature Methods文章（doi:10.1038/nmeth.1401），该技术通过为目标蛋白加入一段特定序列，使得在有植物生长素的情况下，能引发蛋白泛素化降解机制，从而可以人为控制蛋白的降解过程。由于泛素化降解是一个广泛存在于不同物种的机制，这项技术就可以应用于非植物的各种生物体系中。本文通过这项技术，对果蝇的看家基因（house keeping gene）和发育基因（developmental gene）进行了研究，前者普遍表达于所有类型细胞，后者则只在特定组织器官类型的细胞中表达。通过人为控制相应基因的蛋白降解，揭示了两类基因在染色质重塑（chromatin remodelling）及其他相关特征上的差异。
Abstract:
Gene transcription is a highly regulated process in all animals. In Drosophila, two major transcriptional programs, housekeeping and developmental, have promoters with distinct regulatory compatibilities and nucleosome organization. However, it …
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Gene transcription is a highly regulated process in all animals. In Drosophila, two major transcriptional programs, housekeeping and developmental, have promoters with distinct regulatory compatibilities and nucleosome organization. However, it remains unclear how the differences in chromatin structure relate to the distinct regulatory properties and which chromatin remodelers are required for these programs. Using rapid degradation of core remodeler subunits in Drosophila melanogaster S2 cells, we demonstrate that developmental gene transcription requires SWI/SNF-type complexes, primarily to maintain distal enhancer accessibility. In contrast, wild-type-level housekeeping gene transcription requires the Iswi and Ino80 remodelers to maintain nucleosome positioning and phasing at promoters. These differential remodeler dependencies relate to different DNA-sequence-intrinsic nucleosome affinities, which favor a default ON state for housekeeping but a default OFF state for developmental gene transcription. Overall, our results demonstrate how different transcription-regulatory strategies are implemented by DNA sequence, chromatin structure, and remodeler activity.
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