Trends in Cell Biology
A trip to the ER: coping with stress
Section snippets
Sensing the stress: a common role for BiP
The UPR is initiated whenever protein folding in the ER is compromised (Figure 1). Physiological conditions that induce the UPR by causing protein misfolding include: the differentiation and development of professional secretory cells, such as plasma or pancreatic β cells; altered metabolic conditions, such as glucose deprivation, hyperhomocysteinemia and ischemia; mutations in the genes encoding secretory or transmembrane proteins, which normally fold in the ER, such as α-1 antitrypsin and
Temporal control of the UPR: a distinct role for each sensor
Although IRE1, PERK and ATF6 are all activated after dissociation from BiP, the signaling pathways activated by each of these sensors require unique lag times before they become fully activated; consequently, distinct parts of the UPR are regulated by each of these molecules (Figure 2). After exposure to ER stress, the pathway activated most rapidly is translational repression mediated by PERK. Because eIF2α is a direct substrate of PERK, its phosphorylation does not depend on nuclear
Positive and negative feedback loops
As with any pathway of signal transduction, the UPR requires feedback mechanisms to ensure that the response is neither hyperactivated nor turned off prematurely. The two best-characterized negative feedback loops promoting repression of the PERK pathway of the UPR are mediated by GADD34, which is a member of the DNA-damage and growth-arrest-inducible gene family, and p58IPK, a co-chaperone.
GADD34 requires the activation of PERK for its upregulation 19, 25, and its expression is probably
To die or not to die: regulating the transition to apoptosis
In addition to upregulating the genes that support adaptation to and recovery from ER stress, the UPR initiates proapoptotic pathways. However, although some of the molecules and mechanisms involved are identified, little is understood about how they are integrated and able to commit a cell to apoptosis.
In general, the initiation of apoptosis is divided into intrinsic and extrinsic apoptotic pathways, which differ in the activation of the signaling pathways that lead to death [31]. The
ER-stress radiates beyond the immediate realm of protein secretion
The initiation of apoptosis in response to ER stress clearly involves cellular processes, in addition to those strictly involved in protein secretion, and requires interorganellar crosstalk. Signaling pathways radiate from the ER to the nucleus and mitochondria, and probably to other organelles as well. It is becoming apparent that, even during the prosurvival phase of the UPR, the response is far more complex than a simple program of transcriptional upregulation. A question that is now being
Concluding remarks – the future of the UPR
Emphasizing the regulation of the UPR is not meant to imply that understanding the basic pathway lacks only the dotting of ‘i’s and the crossing of ‘t’s. Perhaps there are other sensors of ER stress, as well as new pathways of communication between the ER and other organelles. The emerging interplay between ER stress and the functioning of cellular pathways only tangentially related to protein secretion should also come into sharper focus over the next few years. For example, the mechanistic
Acknowledgements
We thank X. Shen and K. Zhang of the Kaufman laboratory for critically evaluating the manuscript. We apologize to those whose work could only be cited by reference to review articles.
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