C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways.
C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways.
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DOI：
10.1073/pnas.2111262119
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发表时间：
2022-07-05
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
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细胞利用专门的适应性途径来抵消环境变化施加的压力（例如，营养缺乏）或质量控制失败（例如，错误折叠的蛋白质）。这些通路通常在生理环境中被共激活，但连接这些通路的集中机制仍然难以捉摸。使用功能基因组学方法，我们绘制了人类细胞中应激反应途径的组成和相互关系。我们确定了一个保守的因子，HAPSTR 1，它促进细胞和生物体的弹性下的压力条件的显着多样性。HAPSTR 1可被许多应激源诱导，在一条途径中与E3连接酶HUWE 1合作并被其降解，该途径可阻断专门的蛋白毒性、遗传毒性、营养、氧化还原和旁分泌应激反应途径。因此，HAPSTR 1代表了疾病相关应激反应程序的中央协调机制。所有细胞都含有专门的信号通路，使其能够适应特定的分子应激源。然而，这些途径是否在复杂的生理应激状态下受到中枢调控仍不清楚。使用基因组规模的适应性筛选数据，我们量化了739个癌细胞系的应激表型，每个细胞系代表了固有肿瘤应激的独特组合。整合依赖和压力扰动转录组学数据，我们阐明了一个跨越不同压力环境的重要功能基因网络。对这个网络的中央调节因子的分析命名为C16 orf 72/HAPSTR 1，这是一个进化上古老的基因，对依赖于多种应激反应途径的细胞的适应性至关重要。我们发现HAPSTR 1在细胞应激信号传导中起多效性作用，其功能是滴定各种专门的细胞自主和旁分泌应激反应程序。这种功能，而非应激细胞和线虫，是必不可少的弹性存在的压力，从DNA损伤饥饿和蛋白质毒性。从机制上讲，不同的压力诱导HAPSTR 1，它编码的蛋白质表达为两个同样丰富的亚型。在HAPSTR 1同种型之间共享的结构域中的完全保守的残基介导寡聚化和与泛素连接酶HUWE 1的结合。我们发现HUWE 1是HAPSTR 1控制应激信号传导所需的辅因子，反过来，HUWE 1反馈泛素化并使HAPSTR 1不稳定。总而言之，我们认为HAPSTR 1是负责细胞适应性的通路网络中的中央变阻器，其调节可能在人类疾病中具有广泛的用途。
Cells utilize specialized adaptive pathways to counteract stresses imposed by environmental changes (e.g., nutrient scarcity) or quality control failures (e.g., misfolded proteins). These pathways are commonly coactivated in physiological contexts, but centralized mechanisms linking these pathways have remained elusive. Using a functional genomics approach, we mapped the constituents of and relationships between stress response pathways in human cells. We identified a conserved factor, HAPSTR1, which promotes cellular and organismal resilience under a striking diversity of stress conditions. HAPSTR1, inducible by many stressors, both cooperates with and is degraded by the E3 ligase HUWE1 in a pathway that titrates specialized proteotoxic, genotoxic, nutrient, redox, and paracrine stress response pathways. Thus, HAPSTR1 represents a central coordination mechanism for disease-relevant stress response programs. All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease.
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影响因子：
5.3
作者：
Daniely, Y;Dimitrova, DD;Borowiec, JA
通讯作者：
Borowiec, JA
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
12.3
作者：
Dede M;McLaughlin M;Kim E;Hart T
通讯作者：
Hart T
影响因子：
8.8
作者：
Han J;Perez JT;Chen C;Li Y;Benitez A;Kandasamy M;Lee Y;Andrade J;tenOever B;Manicassamy B
通讯作者：
Manicassamy B
影响因子：
56.9
作者：
Hillenmeyer, Maureen E.;Fung, Eula;Giaever, Guri
通讯作者：
Giaever, Guri