An oxygen-sensing network of RNA-binding proteins controls glycolysis via hypoxic translatome remodeling.

ABSTRACT: System-wide remodeling of protein synthesis is a keystone of cellular stress adaptation. Accumulating evidence suggests that changes in protein output (translatome) are controlled predominantly by translational mechanisms that restructure mRNA translation efficiencies (TEs), rather than simple fluctuations in mRNA expression. At the core of this phenomenon lies the key outstanding issue as to the drivers of such stimuli-induced translatome reprogramming, especially from an unbiased, systemic perspective. Oxygen deficiency (hypoxia) is frequently encountered in health and disease. In this study, we report the RNA-binding protein (RBP) nexus that governs oxygen-sensitive translatome reprogramming. Global MATRIX analysis produced an impartial, activity-based blueprint of dynamic RBP utilization, revealing hypoxia-augmented translational activities of HuR hnRNP A2/B1, PCBP1, PCBP2, and PTBP1. Translatome analysis by TMT-pSILAC of each aforementioned RBP revealed a synergistic network that effectuates oxygen-dependent translatome reorganization to enable hypoxic adaptation. Specifically, each RBP is tasked with activating a distinct portfolio of targets and cellular processes that synergistically contribute toward a comprehensive hypoxic response. Notably, the activation of glycolysis and hypoxic cell survival are critically dependent on this RBP network. The hypoxia-inducible factor 2α (HIF-2α) operates as the critical translation-regulating oxygen-sensor that collaborates with this RBP network to regulate mRNA TE and steady-state levels. These observations reveal an RBP/HIF-2α axis that restructures protein output in response to oxygen fluctuations. Conceptually, these findings demonstrate that stress-sensing RBP networks act as gatekeepers of mRNA utilization for global translational remodeling.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jonathan Krieger  

LAB HEAD: Stephen Lee

PROVIDER: PXD011979 | Pride | 2020-07-02

REPOSITORIES: Pride