Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the ‘integrated stress response’ (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC₅₀ = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders.

Life and death and quality control: When cells are subjected to too much stress, they curl up their toes and die. Lu et al. describe a clever strategy cells use to stay alive as long as they are not stressed for too long. The cells' quality-control machinery will activate a so-called death receptor when defective proteins accumulate within the cell, a sign of stress—but they will wait until the proteins have built up for a good long time. If stress is relieved soon enough, levels of the death receptor decay back to normal, and the cells stay alive; otherwise, R.I.P. Science , this issue p. 98

We have combined genome-wide transcription factor binding and expression profiling to assemble a regulatory network controlling the myogenic differentiation program in mammalian cells. We identified a cadre of overlapping and distinct targets of the key myogenic regulatory factors (MRFs)—MyoD and myogenin—and Myocyte Enhancer Factor 2 (MEF2). We discovered that MRFs and MEF2 regulate a remarkably extensive array of transcription factor genes that propagate and amplify the signals initiated by MRFs. We found that MRFs play an unexpectedly wide-ranging role in directing the assembly and usage of the neuromuscular junction. Interestingly, these factors also prepare myoblasts to respond to diverse types of stress. Computational analyses identified novel combinations of factors that, depending on the differentiation state, might collaborate with MRFs. Our studies suggest unanticipated biological insights into muscle development and highlight new directions for further studies of genes involved in muscle repair and responses to stress and damage.

Most of the secreted and plasma membrane proteins are synthesized on membrane-bound ribosomes on the endoplasmic reticulum (ER). They require engagement of ER-resident chaperones and foldases that assist in their folding and maturation. Since protein homeostasis in the ER is crucial for cellular function, the protein-folding status in the organelle's lumen is continually surveyed by a network of signaling pathways, collectively called the unfolded protein response (UPR). Protein-folding imbalances, or "ER stress," are detected by highly conserved sensors that adjust the ER's protein-folding capacity according to the physiological needs of the cell. We review recent developments in the field that have provided new insights into the ER stress-sensing mechanisms used by UPR sensors and the mechanisms by which they integrate various cellular inputs to adjust the folding capacity of the organelle to accommodate to fluctuations in ER protein-folding demands.

The unfolded protein response (UPR) adjusts the cell’s protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α’s ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD’s MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1’s activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.