UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

doi:10.1016/j.tibs.2015.01.002

Trends in Biochemical Sciences

Volume 40, Issue 3, March 2015, Pages 141-148

https://doi.org/10.1016/j.tibs.2015.01.002 Get rights and content

Highlights

•
Autophagy and UPR interaction underlies ERS response outcomes.
•
ERS modulates mitochondrial biogenesis and function.
•
Ubiquitin ligases fine-tune the ERS response.

Cellular stress, induced by external or internal cues, activates several well-orchestrated processes aimed at either restoring cellular homeostasis or committing to cell death. Those processes include the unfolded protein response (UPR), autophagy, hypoxia, and mitochondrial function, which are part of the global endoplasmic reticulum (ER) stress (ERS) response. When one of the ERS elements is impaired, as often occurs under pathological conditions, overall cellular homeostasis may be perturbed. Further, activation of the UPR could trigger changes in mitochondrial function or autophagy, which could modulate the UPR, exemplifying crosstalk processes. Among the numerous factors that control the magnitude or duration of these processes are ubiquitin ligases, which govern overall cellular stress outcomes. Here we summarize crosstalk among the fundamental processes governing ERS responses.

Section snippets

ERS: an overview

The ER is a complex, dynamic organelle whose functions include protein folding, Ca²⁺ storage, and lipid and carbohydrate metabolism. Diverse cellular stresses, such as perturbations in Ca²⁺ homeostasis, redox imbalance, altered protein glycosylation, or protein folding defects, cause unfolded or misfolded proteins to accumulate in the ER lumen, a condition known as ERS. To guard against or respond to ERS, cells have an integrated signaling system to restore homeostasis and normal ER function.

The UPR and autophagy

Autophagy is a major catabolic process that delivers proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. A well-orchestrated program including over 30 autophagy-related (ATG) genes controls autophagy, which can be activated by nutrient starvation and subsequent inhibition of mechanistic target of rapamycin (mTOR) signaling [4] or by the UPR as aggregated misfolded proteins accumulate [5]. A link between autophagy and the UPR has been further

The UPR link with mitochondrial function

Several regulatory components link the UPR with mitochondrial regulation and function. UPR transducers affect mitochondrial regulatory components including ATF4, which was demonstrated to control expression of the ubiquitin ligase Parkin, a crucial regulator of mitochondria function and dynamics [27]. In turn, reciprocal activation is illustrated by the ability of Parkin to enhance select branches of UPR signaling through activation of the sXBP1 pathway [28]. ATF6 is also associated with the

Ubiquitin ligases fine-tune the ERS response

The observation that ubiquitin ligases regulate crosstalk between the UPR, autophagy, and mitochondria suggests that they play a more dominant role within the ERS response than foreseen.

Ubiquitin ligases are central for the ERAD process (reviewed in 9, 10) where they ubiquitylate misfolded proteins, tagging them for proteasomal degradation or removal by autophagy. However, emerging evidence suggests that E3 ubiquitin ligases contribute to the ERS response through mechanisms beyond their role in

Concluding remarks

Under normal growth conditions, concerted action of ERS components is required to maintain cellular homeostasis following external stimuli. Imbalance in these regulatory components, as often seen in pathological conditions, presents a challenge to develop therapies to restore such homeostasis.

Here we indicate the link between UPR-activating conditions, (i.e., hypoxia, ischemia, inflammation, and disruption of ER–mitochondrial contact sites) and the fine balance of the UPR regulatory arms in

Acknowledgments

The authors thank Serge Y. Fuchs, Hyungsoo Kim, Jianfei Qi, and Eric Lau for critical reading of the manuscript. Support by National Cancer Institute (NCI) grant CA128814 to Z.A.R. is gratefully acknowledged. D.S. is supported by a Dr Mildred Scheel Postdoctoral Fellowship from German Cancer Aid.

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Trends in Biochemical Sciences

ReviewUPR, autophagy, and mitochondria crosstalk underlies the ER stress response

Highlights

Section snippets

ERS: an overview

The UPR and autophagy

The UPR link with mitochondrial function

Ubiquitin ligases fine-tune the ERS response

Concluding remarks

Acknowledgments

Curr. Opin. Cell Biol.

Cell

Redox Biol.

Mol. Cell

Biochim. Biophys. Acta

Cell. Signal.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Exp. Gerontol.

Trends Endocrinol. Metab.

Cell Metab.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Trends Biochem. Sci.

Mol. Cell

Trends Biochem. Sci.

Cell Rep.

Cell

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Mol. Cell

Blood

Cell

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Biochim. Biophys. Acta

Cell. Signal.

The unfolded protein response: controlling cell fate decisions under ER stress and beyond

Nat. Rev. Mol. Cell Biol.

Regulation of basal cellular physiology by the homeostatic unfolded protein response

J. Cell Biol.

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

Cell. Mol. Life Sci.

The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression

Nucleic Acids Res.

Paneth cells as a site of origin for intestinal inflammation

Nature

Cleaning up in the endoplasmic reticulum: ubiquitin in charge

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J. Cell Biol.

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Am. J. Physiol. Gastrointest. Liver Physiol.

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Oncogene

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Oncogene

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Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells

Sci. Signal.

Review
UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

Retention of mutant α₁-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response