Trends in Cell Biology
ReviewBidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling
Introduction
Cell growth, proliferation, survival, and energetic maintenance are intimately connected processes. External signals such as nutrient availability, growth factors, or inflammatory mediators are decoded by cellular sentinels, which – where appropriate – can remodel cell physiology. Thus, cells respond to positive growth signals by promoting anabolism (i.e. the build-up of macromolecules and the inhibition of degradative reactions) and to unfavorable growth conditions by eliciting stress pathways. The mTOR signaling pathways and the ER stress response (the so-called ‘unfolded protein response’, UPR) play increasingly recognized roles in this interplay 1, 2. These two signaling networks have traditionally been considered as separate pathways, and the identification of mTOR–UPR interconnections, which is reviewed herein, is a relatively new area of research.
The atypical serine/threonine kinase mTOR is a master regulator of cell growth and metabolism. It exists in two complexes, mTORC1 and mTORC2, which exhibit different subunit compositions and execute distinct cellular tasks 3, 4 (Box 1, Box 2). mTOR complexes reside in the cytoplasm, where they are often found in association with cellular membranes (see sections ‘Signal integration by mTORC1’ and ‘mTORC2 and the ER’). Several pathways downstream of the mTOR complexes are known [4] and new ones are constantly being discovered. The UPR, on the other hand, is a conglomeration of signaling pathways originating from the ER (Box 3). It is known to be triggered when the protein-folding capacity in the ER is overwhelmed and ‘ER stress’ ensues. The membrane-bound network of the ER, which extends from the nuclear envelope to the periphery of the cell and maintains vital contact zones with many other cell organelles, is a highly metabolic organelle [1]. It mediates many anabolic processes such as lipid synthesis, gluconeogenesis, and the biogenesis of peroxisomes and lipid droplets, and also the catabolic turnover of proteins and organelles through autophagy or proteasomal hydrolysis.
Signaling through mTORC1 and mTORC2 is activated by extracellular and intracellular cues when conditions are favorable for growth. Both mTOR complexes in turn facilitate cell growth, survival, and proliferation (Box 1, Box 2). The metabolic classification of the UPR stress pathway is less straightforward, because it would be a gross oversimplification to state that it generally antagonizes cellular anabolism, which is orchestrated by mTOR. Indeed, the UPR not only signals stress, catabolism, and cell death [5], but also, for instance, the anabolic expansion of ER membranes [6]. In the same vein, activation of the UPR is also achieved by stimuli that are not necessarily linked to unfavorable (‘stressful’) growth conditions (see section ‘Upstream of the UPR’).
Given their central influence on cell viability, both mTOR and UPR have been subject to extensive biomedical and pharmacological research activity 7, 8, 9, for instance in the search for new cancer treatments. Thus, evaluating and understanding the intersections and synergisms (or antagonisms) between the outputs of mTOR and UPR is of importance; possible routes of crosstalk between these signaling networks are fundamental for cell health. Here, we do not intend to provide a comprehensive synopsis of the upstream and downstream signaling networks surrounding mTOR and UPR, for which the reader is referred to other recent articles 3, 4, 5, 10. Instead, this review focuses on the interdependence of these two pathways in health and disease. Recent pioneering studies on molecular links between mTORC1, mTORC2, and the ER stress response will be summarized along with a tentative preview of where these new insights may guide future therapeutic strategies.
Section snippets
Signal integration by mTORC1
Our understanding of the molecular mechanisms leading to the activation of mTORC1 has tremendously increased over the past few years. Known pathways culminate in the association of mTORC1 with the active, GTP-bound forms of the small GTPases Rheb and Rag which initiate mTORC1 signaling [11]. Thus, mTORC1 activation is regulated by at least two independent inputs. One is the regulation of the GTP-binding status of Rheb in response to growth factors. The other is the GTP loading of Rag and the
Upstream of the UPR
A growing body of evidence places the UPR downstream of physiological stimuli that do not necessarily act via the accumulation of unfolded proteins in the ER [10]. For instance, similarly to mTORC1, the UPR is sensitive to the availability of nutrients and growth signals [1]. Indeed, the historically oldest way to elicit the UPR (at that time measured by the increased synthesis of ‘glucose regulated proteins’) was glucose starvation [22], illustrating that the responsiveness of the ER to a low
Links between mTORC1 and UPR
The primary output of UPR signaling is homeostatic adaptation by a variety of mechanisms that aim at restoring ER function (Box 3). As a secondary output, however, the UPR can also switch to promote apoptotic cell death through multiple pathways that remain to be understood fully [5]. Notably, the UPR as a mediator of ER-stress-induced apoptosis plays a pivotal role in a host of pathological conditions including neurodegenerative misfolding diseases and oxidative injury, as reviewed elsewhere 9
mTORC2 and the ER
In contrast to mTORC1, much less is known about pathways operating upstream of mTORC2. However, ER stress also impacts upon mTORC2 signaling. Pharmacological induction of ER stress for several hours leads to GSK3β-catalyzed phosphorylation of the mTORC2 component rictor, which suppresses Akt activation [74]. Thus, together with the negative regulation of mTORC2 by the mTORC1 effector S6K1 [75], this mechanism probably contributes to the chronic UPR–mTORC1 apoptosis pathway described above.
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Therapeutic implications and future directions
The connections and interdependencies between mTORC1 and UPR during chronic responses are associated with various pathologies 43, 45, 46, 47, 48. As a consequence, several new clues for combined therapy ensue; these warrant detailed preclinical evaluations and are discussed in this section.
A first example is TSC [16], a multisystem disorder which is caused by constitutive activation of mTORC1 and includes the activation of ER stress pathways 41, 43, 45, 53. The most frequent medical symptom
Concluding remarks
In summary, several recent reports have shed light on new connections that link two hitherto separated areas of modern cell biology. During the course of this review we have discussed both physiological and therapeutic implications of these findings. Considering that the field of combined mTOR/UPR research is new, significant progress is probably still ahead.
Acknowledgments
We thank Don Benjamin for critical review of the manuscript. Funding by the Canton of Basel, the Swiss National Science Foundation (C.A.H. and M.N.H.), the August Collin-Fonds (C.A.H.), and the Louis-Jeantet Foundation (M.N.H.) is gratefully acknowledged.
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