Regulation of translation during the unfolded protein response (UPR)

The endoplasmic reticulum (ER) is the main cellular compartment in protein folding and maturation with about one third of the proteome being synthesized at the ER. Perturbations that alter the function of this compartment often result in the accumulation of unfolded or misfolded proteins resulting in a condition referred to as ER stress. This triggers an adaptive signal transduction pathway, the Unfolded Protein Response (UPR), that aims to reinstate cellular homeostasis, and, if that fails, to trigger apoptosis.

Part of the UPR involves translational reprogramming by the PKR-like endoplasmic reticulum kinase (PERK) that phosphorylates the eukaryotic initiation factor 2 alpha (eIF2α) to limit its recycling.  This results in a global attenuation of cellular translation. However, a sub-group of mRNAs exhibits increased translation under conditions of eIF2α phosphorylation. These messages usually bear special features within their 5’ leader sequences (internal ribosome entry sites, or certain arrangements of upstream open reading frames) that drive protein synthesis when ‘canonical’ translation initiation is impaired. Our aim is to comprehensively identify RNAs that exhibit increase translation under stress and to study their regulation in molecular detail.

To gain a better understanding of the UPR we use a multi-omics approach together with the labs of R. Ahrends (ISAS Dortmund), B. Tews (DKFZ Heidelberg), G. Tödt ( EMBL Heidelberg), and C. Knobbe-Thomsen (Heinrich-Heine University Düsseldorf) that aims to generate comprehensive datasets of the UPR in cellular models.


Analysis of transcriptomic and proteomic changes after induction of the UPR in glioblastoma cells.