Review
Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling

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Many cellular processes including apoptosis, autophagy, translation, energy metabolism, and inflammation are controlled by the mammalian target of rapamycin (mTOR) kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR). Although both of these signaling nodes have attracted wide attention in fundamental cell biology and drug discovery, crosstalk between the two pathways has emerged only very recently. mTOR complex 1 (mTORC1) operates both upstream and downstream of ER stress signals, which can either enhance or antagonize the anabolic output of mTORC1. Upon prolonged ER stress, mTORC1 contributes to apoptotic signaling by suppressing the survival kinase Akt through feedback inhibition. Likewise, chronic ER stress obstructs activation of Akt by mTOR complex 2. This review surveys our knowledge of mTOR–ER stress intersections and highlights potential therapeutic implications.

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.

Does

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.

References (89)

  • E. van Anken

    Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion

    Immunity

    (2003)
  • K.T. Pfaffenbach

    Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver

    J. Nutr.

    (2010)
  • S. Matus

    Protein folding stress in neurodegenerative diseases: a glimpse into the ER

    Curr. Opin. Cell Biol.

    (2011)
  • U. Ozcan

    Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis

    Mol. Cell

    (2008)
  • N. Ito

    mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome

    Lab. Invest.

    (2011)
  • M.J. Jurczak

    Dissociation of inositol requiring enzyme (IRE1alpha)-mediated JNK activation from hepatic insulin resistance in conditional X-box binding protein-1 (XBP1) knockout mice

    J. Biol. Chem.

    (2012)
  • T. Nakamura

    Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis

    Cell

    (2010)
  • S. Karassek

    Ras homolog enriched in brain (Rheb) enhances apoptotic signaling

    J. Biol. Chem.

    (2010)
  • P. Hu

    Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death

    J. Biol. Chem.

    (2004)
  • T. Hosoi

    Akt up- and down-regulation in response to endoplasmic reticulum stress

    Brain Res.

    (2007)
  • T.R. Peterson

    mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway

    Cell

    (2011)
  • A.C. Hsieh

    Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP–eIF4E

    Cancer Cell

    (2010)
  • D.R. Boulbes

    Endoplasmic reticulum is a main localization site of mTORC2

    Biochem. Biophys. Res. Commun.

    (2011)
  • V. Zinzalla

    Activation of mTORC2 by association with the ribosome

    Cell

    (2011)
  • P. Polak

    Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration

    Cell Metab.

    (2008)
  • N. Morishima

    Activating transcription factor-6 (ATF6) mediates apoptosis with reduction of myeloid cell leukemia sequence 1 (Mcl-1) protein via induction of WW domain binding protein 1

    J. Biol. Chem.

    (2011)
  • P. Polak et al.

    mTORC2 Caught in a SINful Akt

    Dev. Cell

    (2006)
  • K. Inoki

    TSC2 mediates cellular energy response to control cell growth and survival

    Cell

    (2003)
  • Y. Cao

    Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway

    J. Biol. Chem.

    (2006)
  • R. Zoncu

    mTOR: from growth signal integration to cancer, diabetes and ageing

    Nat. Rev. Mol. Cell Biol.

    (2011)
  • I. Tabas et al.

    Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress

    Nat. Cell Biol.

    (2011)
  • S. Schuck

    Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response

    J. Cell Biol.

    (2009)
  • D. Benjamin

    Rapamycin passes the torch: a new generation of mTOR inhibitors

    Nat. Rev. Drug Discov.

    (2011)
  • I. Kim

    Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities

    Nat. Rev. Drug Discov.

    (2008)
  • D.T. Rutkowski et al.

    Regulation of basal cellular physiology by the homeostatic unfolded protein response

    J. Cell Biol.

    (2010)
  • R.V. Duran et al.

    Regulation of TOR by small GTPases

    EMBO Rep.

    (2012)
  • K. Inoki

    TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

    Nat. Cell Biol.

    (2002)
  • P.B. Crino

    The tuberous sclerosis complex

    N. Engl. J. Med.

    (2006)
  • Y. Sancak

    The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1

    Science

    (2008)
  • E. Kim

    Regulation of TORC1 by Rag GTPases in nutrient response

    Nat. Cell Biol.

    (2008)
  • R. Zoncu

    mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H-ATPase

    Science

    (2011)
  • C.E. Moore

    PERK activation at low glucose concentration is mediated by SERCA pump inhibition and confers preemptive cytoprotection to pancreatic beta-cells

    Mol. Endocrinol.

    (2011)
  • B.G. Wouters et al.

    Hypoxia signalling through mTOR and the unfolded protein response in cancer

    Nat. Rev. Cancer

    (2008)
  • T. Ramming et al.

    The physiological functions of mammalian endoplasmic oxidoreductin 1 (Ero1): on disulfides and more

    Antioxid. Redox Signal.

    (2012)
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