嘌呤体作为代谢物，通过在应激条件下划分 DNPS 酶来提高从头嘌呤合成 (DNPS) 的效率。然而，嘌呤体组装的机制及其病理生理功能仍然难以捉摸。在这里，我们表明，通过 cullin-5/锚蛋白重复序列​​和含有 11 (Cul5/ASB11) 泛素连接酶的 SOCS 盒对 DNPS 酶磷酸核糖氨基咪唑羧化酶和磷酸核糖氨基咪唑琥珀酰胺合成酶 (PAICS) 进行 K6 多泛素化，在嘌呤体组装中发挥驱动作用。在几种嘌呤体诱导信号下，ASB11 通过解除 H3K9me3/HP1α 介导的转录沉默而上调，从而刺激 PAICS 多泛素化。多泛素化 PAICS 招募泛素相关蛋白 2 (UBAP2)，这是一种具有多段固有无序区域的泛素结合蛋白，从而诱导相分离以触发嘌呤体组装，从而增强 DNPS 途径通量。在人类黑色素瘤中，ASB11 高度表达，以促进组成型嘌呤体的形成，黑色素瘤细胞对其成瘾，以支持其在异种移植模型中的增殖、活力和肿瘤发生。我们的研究确定了嘌呤体组装响应细胞应激的驱动机制，并揭示了嘌呤体形成对人类恶性肿瘤的影响。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.Copyright © 2023 Elsevier Inc. All rights reserved.