What is the function of Ire1 in the cell?

IRE1 is an ER transmembrane sensor that activates UPR to maintain ER and cellular function. While mammalian IRE1 promotes cell survive, it can initiate apoptosis via decay of anti-apoptotic microRNAs.

How does thapsigargin induced ER stress?

ER stress can be induced by treating cells with 0.1–1 µM of thapsigargin for 5 hours. Brefeldin A inhibits transport of proteins from the ER to the Golgi and induces retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum. This leads to the accumulation of unfolded proteins in the ER.

What causes endoplasmic reticulum stress?

ER stress may be caused by factors that impair protein glycosylation or disulfide bond formation, or by overexpression of or mutations in proteins entering the secretory pathway. Ultimately, signaling from these stress-sensing proteins protects the cell or, alternatively, promotes cell death.

How is Ire1 activated?

Ire1 is activated in response to accumulation of misfolded proteins within the endoplasmic reticulum as part of the unfolded protein response (UPR). It is a unique enzyme, possessing both kinase and RNase activity that is required for specific splicing of Xbp1 mRNA leading to UPR activation.

How is IRE1 regulated by BiP?

One model proposes that Ire1 activity is mainly regulated by the ER-resident chaperone BiP (Kar2 in yeast). In this model, BiP inhibits Ire1 activity by binding to it in the absence of stress. During stress, BiP is titrated away by unfolded proteins, leaving Ire1 free to oligomerize and activate.

How do you detect ER stress?

Generally ER stress is detected indirectly by measuring the levels of specific UPR factors. Commonly measured indicators of UPR activation include; phosphorylated PERK, phosphorylated eIF2α, Gadd153/CHOP, ATF4, Grp78/BiP, Grp94, calreticulin, and protein disulphide isomerase (PDI).

What’s the chemical used to induce ER stress?

Three chemicals are generally used to experimentally induce ER stress: tunicamycin (Sigma), thapsigargin (Sigma), and Brefeldin A (BFA) (Sigma). Although these chemicals target different components of the ER, their common effect is to interfere with ER functions and thereby lead to ER protein misfolding.

How can a cell recover from ER stress?

The ESR acts to restore normal ER homeostasis and is therefore cytoprotective. However, when a stress is so strong or persistent that ER dysfunction cannot be corrected, metazoan cells can initiate apoptosis, allowing the regulated destruction of cells that are irreparably damaged or a risk to the organism as a whole.

Why is the smooth ER important?

The smooth ER is involved in the synthesis of lipids, including cholesterol and phospholipids, which are used in the production of new cellular membrane. In certain cell types, smooth ER plays an important role in the synthesis of steroid hormones from cholesterol.

How is Ire1 regulated by BiP?

What are the consequences of unfolded protein response signaling?

This UPR signaling is adaptive and restored the normal function of cells by decreasing protein synthesis, increasing the folding capacity of ER and degradation of misfolded proteins. If the stress condition is overwhelmed, then UPR signaling shifts to apoptotic pathways.

What is an unfolded protein called?

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum.

What does IRE1 do in response to ER stress?

In response to ER stress, IRE1 oligomerizes to activate an endoribonuclease domain that splices the mRNA encoding the transcription factor HAC1 (homologous to ATF/CREB) in yeast [ 6, 7] or XBP1 (X-box binding protein 1) in metazoans [ 8, 9 ].

How does the UPR trigger the ER stress response?

The accumulation of unfolded proteins triggers the ER stress response (UPR), which allows cells to fight against fluctuations in protein expression under both physiological and pathological conditions. Severe acute ER stress responses can be induced by drug treatment.

How does p38-ire1-xbp1 affect the stress response?

The p38 MAPK directly acts on the phosphorylation of IRE-1 to promote the stress response. Meanwhile, the insulin receptor function through autophagy activation to counteract the p38-IRE-1-XBP-1 pathway. Together, these results reveal an intricate cellular regulatory network in response to chronic stress in multicellular organism.

How does SIRT1 protect the heart from stress?

Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective.