Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

  title={Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase},
  author={Heather P. Harding and Yuhong Zhang and David Ron},
Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2α (eIF2α) in response to a stress signal from the endoplasmic reticulum (ER),. Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene… 

A Novel Feedback Loop Regulates the Response to Endoplasmic Reticulum Stress via the Cooperation of Cytoplasmic Splicing and mRNA Translation

A model in which eIF2α phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress is proposed.

Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK

It is reported that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex, and this switch correlates with a marked change to the protease sensitivity pattern, indicative of a major conformational change in the PERK kinase domain upon activation.

Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

The UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA, suggesting that this pathway may be broadly utilized by stresses that activate eIF2α kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.

The double-stranded RNA-activated protein kinase PKR is dispensable for regulation of translation initiation in response to either calcium mobilization from the endoplasmic reticulum or essential amino acid starvation.

The results show that PKR is not required for increased eIF2alpha phosphorylation or inhibition of protein synthesis under conditions promoting the UPR or in response to amino acid deprivation.

The structure of the PERK kinase domain suggests the mechanism for its activation.

The crystal structure of PERK's kinase domain suggests conservation in the mode of activation of eIF2α kinases and is consistent with a `line-up' model for PERK activation triggered by oligomerization of its luminal domain.

Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.

It is proposed that ER stress-induced proteolysis of membrane-bound p90 ATF6 releases soluble p50ATF6, leading to induced transcription in the nucleus, similar to that reported for cholesterol homeostasis.

The Protein Kinase/Endoribonuclease IRE1α That Signals the Unfolded Protein Response Has a Luminal N-terminal Ligand-independent Dimerization Domain*

The N-terminal luminal domains of IRE1 and PERK sense ER stress conditions by a common mechanism and transmit the signal to regulate the cytoplasmic domains of these receptors, and it is demonstrated that the NLD forms stable dimers linked by intermolecular disulfide bridges.

Regulation of Sumo mRNA during Endoplasmic Reticulum Stress

It is shown that Smt3, a homolog of small ubiquitin-like modifier (sumo), is a non-canonical RIDD target in Drosophila S2 cells and unlike other RIDd targets, the sumo transcript does not stably associate with the ER membrane, but instead relies on an Xbp1-like stem loop and a second UPR mediator, Perk, for its degradation during stress.

Nck in a Complex Containing the Catalytic Subunit of Protein Phosphatase 1 Regulates Eukaryotic Initiation Factor 2α Signaling and Cell Survival to Endoplasmic Reticulum Stress*

It is demonstrated that the Src homology (SH) domain-containing adaptor Nck is a key component of a molecular complex that controls eIF2α phosphorylation and signaling in response to ER stress and contributes to maintain eif2α in a hypophosphorylated state.

Modulation of the Eukaryotic Initiation Factor 2 α-Subunit Kinase PERK by Tyrosine Phosphorylation*

PerK is classified as a dual specificity kinase whose regulation by tyrosine phosphorylation contributes to its optimal activation in response to ER stress.



A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells.

HIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells and is demonstrated to be highly conserved to the yeast counterpart having a Ser/Thr protein kinase domain and a domain homologous to RNase L.

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.

The Unfolded Protein Response Pathway in Saccharomyces cerevisiae

It is shown that the cytoplasmic domain of Ire1p receptor indeed has intrinsic Ser/Thr kinase activity and contains Ser/ Thr phosphorylation sites as well and is shown to form oligomers in vivo and in vitro.

Calcium Depletion from the Endoplasmic Reticulum Activates the Double-stranded RNA-dependent Protein Kinase (PKR) to Inhibit Protein Synthesis (*)

The data show that calcium depletion activates PKR to phosphorylate eIF-2α, and this activation is likely mediated through the PKR RNA binding domain.

Independent Signaling of grp78 Gene Transcription and Phosphorylation of Eukaryotic Initiation Factor 2α by the Stressed Endoplasmic Reticulum (*)

It is concluded that signaling of grp78 gene transcription can occur independently of eif-2α phosphorylation or translational repression and that greater degrees of ER stress are required for eIF-2 α phosphorylated than for grp 78 mRNA induction.

Activation of the Double-stranded RNA-regulated Protein Kinase by Depletion of Endoplasmic Reticular Calcium Stores (*)

Findings suggest that PKR mediates the translational suppression occurring in response to perturbation of ER Ca homeostasis.

The eIF-2α kinases: regulators of protein synthesis in starvation and stress

Phosphorylation of translation initiation factor 2α is a highly conserved mechanism for down-regulating protein synthesis in response to starvation or stress and eIF-2α kinase DAI is an important component of the interferon response.

Identification and Characterization of Pancreatic Eukaryotic Initiation Factor 2 α-Subunit Kinase, PEK, Involved in Translational Control

Using recombinant PEK produced inEscherichia coli or Sf-9 insect cells, it is demonstrated that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2α on serine-51.