GSE158249
A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress
Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by induction of distinct gene programs tailored to each stress condition. Although the mechanisms that lead to general repression of protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here we show that the noncanonical 5' cap-binding protein eIF3d is specifically activated in response to metabolic stress, due to loss of CK2-mediated phosphorylation near the eIF3d cap-binding pocket. Activated eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mTOR pathway, and eIF3d-mediated translation adaptation is essential for cell survival during chronic glucose deprivation. Our findings reveal a new mechanism of translation reprogramming engaged in response to metabolic stress. Overall design: eIF3dTEV-293T cells were grown in complete or glucose-free media for 48 h prior to harvest. Cells were crosslinked with UV 254 nm light, and eIF3d was isolated using anti-HA magnetic beads. eIF3d was released from the eIF3 complex by TEV protease digestion.