The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells

Abstract

Cardiac development involves large‐scale rearrangements of the proteome. How the developing cardiac cells maintain the integrity of the proteome during the rapid lineage transition remains unclear. Here it is shown that proteotoxic stress visualized by the misfolded and/or aggregated proteins appears during early cardiac differentiation of human pluripotent stem cells and is resolved by activation of the PERK branch of unfolded protein response (UPR). PERK depletion increases misfolded and/or aggregated protein accumulation, leading to pluripotency exit defect and impaired mesendoderm specification of human pluripotent stem cells. Mechanistically, it is found that PERK safeguards mesendoderm specification through its conserved downstream effector ATF4, which subsequently activates a novel transcriptional target WARS1, to cope with the differentiation‐induced proteotoxic stress. The results indicate that protein quality control represents a previously unrecognized core component of the cardiogenic regulatory network. Broadly, these findings provide a framework for understanding how UPR is integrated into the developmental program by activating the PERK‐ATF4‐WARS1 axis.

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

“…The inhibition of GADD34 getsdiminished in autophagy-dependent survival suggesting that GADD34 has a positive effect on autophagy induction [75][76][77]. Additionally, it is able to down-regulate apoptotic cell death via mTOR inhibition during ER stress PERK−/− cells are hypersensitive to the lethal effect of ER stress, suggesting their essential role in the stress-response mechanism [68,69]. The active PERK is able to phos-phorylate the translation initiation factor eiF2α (eukaryotic translation initiation factor 2α), which becomes a potent allosteric inhibitor of eIF2B [70].…”