期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：27
DOI：10.1073/pnas.2111262119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
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.
