Endoplasmic recticulum stress

The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field.

The ER fulfills multiple cellular functions (1,2).The lumen of the ER is a unique environment, containing the highest concentration of Ca²⁺ within the cell because of active transport of calcium ions by Ca²⁺ ATPases. The lumen is an oxidative environment, critical for formation of disulfide bonds and proper folding of proteins destined for secretion or display on the cell surface. Because of its role in protein folding and transport, the ER is also rich in Ca²⁺-dependent molecular chaperones, such as Grp78, Grp94, and calreticulin, which stabilize protein folding intermediates (3,4,5).

Environment

Many disturbances, including those of cellular redox regulation, cause accumulation of unfolded proteins in the ER, triggering an evolutionarily conserved response, termed the unfolded protein response (UPR). Glucose deprivation also leads to ER stress, by interfering with N-linked protein glycosylation. Aberrant Ca²⁺ regulation in the ER causes protein unfolding, because of the Ca²⁺-dependent nature of Grp78, Grp94, and calreticulin (6). Viral infection may also trigger the UPR, representing one of the ancient evolutionary pressures for linking ER stress to cell suicide in order to avoid spread of viruses. Further, because a certain amount of basal protein misfolding occurs in the ER, normally ameliorated by retrograde transport of misfolded proteins into the cytosol for proteasome-dependent degradation, situations that impair proteasome function can create a veritable protein traffic jam and can even cause inclusion body diseases associated with neurodegeneration.

Recent findings:

In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits.

Footnotes

1. Schroder, M, Kaufman, RJ. ER stress and the unfolded protein response. Mutat. Res. 2005. 569:29-63. View this article via: PubMed

2. 2Shen, X, Zhang, K, Kaufman, RJ. The unfolded protein response: a stress signaling pathway of the endoplasmic reticulum [review]. J. Chem. Neuroanat. 2004. 28:79-92. View this article via: PubMed

3. Rao, RV, Ellerby, HM, Bredesen, DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004. 11:372-380. View this article via: PubMed

4. Breckenridge, DG, Germain, M, Mathai, JP, Nguyen, M, Shore, GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene. 2003. 22:8608-8618. View this article via: PubMed

5. Orrenius, S, Zhivotovsky, B, Nicotera, P. Regulation of cell death: the calcium-apoptosis link [review]. Nat. Rev. Mol. Cell Biol. 2003. 4:552-565.

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6. Ma, Y, Hendershot, LM. ER chaperone functions during normal and stress conditions. J. Chem. Neuroanat. 2004. 28:51-65.

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7. Sree R. Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness.Skeletal Muscle20133:13.DOI: 10.1186/2044-5040-3-13.Rayavarapu et al.; licensee BioMed Central Ltd. 2013