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Cell biology

How to combat stress

Life is full of stress, and all life forms — from bacteria to humans — have evolved ways of sensing and responding to it. The latest findings shed light on how cells deal with stress.

In cells, protein homeostasis — a delicate balance between maintaining protein conformations, refolding misfolded proteins and degrading damaged proteins — is normally maintained by regulatory networks that control protein synthesis and degradation. Moreover, molecular chaperones are key players in protein homeostasis, helping proteins to fold and preventing aggregation of misfolded proteins, which could have substantial, disease-related consequences1,2. So when environmental stress such as nutrient deprivation or oxygen shortage disrupts protein homeostasis, the cell responds. Nowhere is this process more exquisitely controlled than in the endoplasmic reticulum, an extensive organelle consisting of interconnecting tubules that serves as the synthesis site for secretory and membrane proteins. In two fascinating studies from the same group, published in this issue, Korennykh et al.3 (page 687) and Aragón et al.4 (page 736) show that stress elicits the assembly at the endoplasmic reticulum of signalling centres that sense the accumulation of unfolded proteins and direct the appropriate response.

When stress begins to take its toll in a cell and unfolded proteins accumulate, the transmembrane protein Ire1p seems to be the first point of call. The domain of this protein that faces the lumen of the endoplasmic reticulum binds to unfolded proteins there. Its cytoplasmic domain has endonuclease enzymatic activity, and so can cleave the messenger RNA for the vital stress-response protein Hac1p at two specific locations. The result is removal of a domain that prevents Hac1p synthesis, and the rejoining of the two mRNA fragments, to yield an mRNA that can then be efficiently translated5.

In the first of the two papers, Korennykh et al.3 present a compendium of structural biology and biochemical studies on the Ire1p cytoplasmic domain. What they propose is remarkable: a transmembrane communication event that promotes oligomerization of the cytoplasmic domain into an unusual extended helical rod, much like a DNA double helix. Consequently, the cytoplasmic domain can function as both a kinase and an endonuclease. The authors' structural models are provocative, as they suggest that supramolecular organization is necessary for Ire1p transition to an active, stress-signalling state.

The structure of Ire1p was also reported by another group last year6. Although there are clear similarities in the two structures3,6, the differences are substantial. Unlike Korennykh and colleagues' proposal that higher-order oligomerization is required for activation of the Ire1p cytoplasmic domain, the earlier structure indicated a requirement for a back-to-back dimer arrangement. This inconsistency probably reflects relatively modest differences in the precise domains selected in each study, although Korennykh et al. provide mechanistic support for the validity of their model with detailed biochemical studies. In the rest of my article, however, I will focus on the biology of the cellular response to stress-associated accumulation of unfolded proteins.

Aragón et al.4 demonstrate that, on sensing unfolded proteins in the lumen of the endoplasmic reticulum, Ire1p molecules coalesce into large, interacting clusters, and at the same time their cytoplasmic domain becomes active. But captivating questions in the story of the unfolded-protein response are manifold, and the authors provide a surprising answer to one of the more vexing ones: how do Ire1p clusters interact with the HAC1 mRNA?

The first clue came with the observation that regions in HAC1 mRNA outside the sites cleaved by Ire1p are necessary for the stress response in vivo, but not for mRNA processing in vitro. The authors4 identify one such key region, which they call the 3′ bipartite element (Fig. 1). They find that, in stressed yeast cells, HAC1 mRNA lacking the 3′ bipartite element interacts with Ire1p clusters only weakly, if at all. Consequently, a rather dismal unfolded-protein response is elicited and the stressed cells cannot sustain growth.

Figure 1: Emergency response at the endoplasmic reticulum.

a, In the unstressed cell, protein folding within the endoplasmic reticulum occurs efficiently; the unfolded protein sensor and signalling protein Ire1p is inactive, and the HAC1 messenger RNA remains untranslated in the cytoplasm. b, Under stress, protein folding is disrupted and unfolded proteins accumulate in the endoplasmic reticulum. It emerges3,4 that the binding of unfolded proteins to Ire1p promotes clustering of this protein and activation of the endonuclease activity of its cytosolic domain. HAC1 mRNAs, themselves attached to multiple ribosomes, are then recruited to the activated Ire1p clusters, and are processed there, allowing translation of the essential stress-response factor Hac1p protein.

Intriguingly, for the 3′ bipartite element to direct HAC1 mRNA to the clusters of activated Ire1p, translation of HAC1 mRNA must be repressed. Aragón et al.4 provide a satisfying answer to why this might be so: with mRNA processing linked to translational repression, only those mRNAs that contain the inhibitory domain find their way to Ire1p clusters. This paradigm provides the first example of mRNA localization serving as a crucial regulatory switch.

As for the remaining questions, perhaps the most compelling is how HAC1 mRNAs find their way to activated Ire1p signalling clusters. Aragón et al. speculate that HAC1 mRNAs travel from their cytoplasmic location along cytoskeletal filaments to these signalling sites at the endoplasmic reticulum. This is an attractive idea, and regulation of mRNA localization by the cytoskeleton and molecular motors certainly has ample precedent. But would it mean that activated Ire1p clusters also serve as sites for the attachment of cytoskeletal filaments?

And, once on the endoplasmic reticulum, what serves as the binding partner for HAC1 mRNA? After all, the vast majority of mRNA localization signals are recognized by proteins that contain evolutionarily conserved RNA recognition motifs. So it is the complex of mRNA and RNA-binding protein that directs the localization event. Korennykh et al.3 provide intriguing speculation on this question. They propose that conformational changes in Ire1p that allow its clustering and activation also create a direct binding site for HAC1 mRNA — potentially another remarkable twist in the biology of mRNA localization.

But if activated Ire1p provides both the binding site for the 3′ bipartite element and the enzymatic function necessary for the HAC1 mRNA processing upstream of this element, how do unprocessed HAC1 mRNAs gain access to activated signalling centres? One possibility is that Ire1p-processed HAC1 mRNAs are poor Ire1p binding partners, and simply diffuse away. Yet the data presented4 indicate seemingly stable co-localization of HAC1 mRNAs with the active Ire1p clusters. Perhaps there are other binding partners for the HAC1 mRNA on the endoplasmic reticulum. Many mRNAs that don't encode secretory or membrane proteins are localized to the endoplasmic reticulum and are translated on ribosomes bound to this organelle7. Given this precedent, might the unprocessed HAC1 mRNAs initially bind to separate sites on the endoplasmic reticulum membrane and be rapidly, and reversibly, transferred to Ire1p signalling clusters? The kinetics of surface chemistry would favour this latter possibility, as reactions occur significantly faster when constrained to a two-dimensional surface rather than in the three dimensions of a solution.

From these lines of questioning, one point should be clear. These ground-breaking studies3,4 have created both fertile territory for research into the regulation of mRNA localization and mRNA-mediated signalling, and opportunities to gain insights into the fundamental mysteries of the cellular response to environmental stress. The unfolding story of the stress response in the endoplasmic reticulum has yielded many a new paradigm; these latest findings give every indication that the store of surprises is far from exhausted.


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Nicchitta, C. How to combat stress. Nature 457, 668–669 (2009).

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