33. Endoplasmatic reticulum

Functions of ER

ER contains the enzymes of many metabolic processes. G6Pase is found there, fatty acid elongation and desaturation, triglyceride synthesis, cholesterol and isoprenoid synthesis, ACAT, lipoprotein synthesis and phospholipid synthesis all take place in the ER.

ER is involved in other things as well. The cytochrome P450 system is found in ER and is involved in the phase I. of biotransformation. Glucuronidation also takes place in the ER and is involved in phase II. of biotransformation.

The ER also acts as a Ca2+ storage, with 5mM of Ca2+ being found there, which is five times higher than the concentration of Ca2+ in the cytosol.

ER is also involved in the feedback inhibition of cholesterol synthesis, by the function of SCAP and SREBP.

ER stress

Several factors will stress the ER, like when there is not enough glucose to glycosylate proteins, when the Ca2+ content in the ER drops, when the ER lumen becomes too reductive, or when there is an overproduction of proteins. The ER responds to this stress by increasing its volume and decrease its protein synthesis.

Many disorders are characterized by ER stress, like Alzheimer’s, Parkinson’s and type 1 diabetes.

Unfolded protein response (UPR)

The UPR is a response to an accumulation of misfolded proteins in the ER. The ER senses that many proteins are misfolded and responds. The UPR results in four outcomes: Inhibiting protein synthesis, increasing the number of chaperones and activating ER-dependent protein degradation. If none of that helps, it will induce apoptosis.

Several proteins are involved in the UPR. IRE1, PERK and ATF6 sense whether misfolded proteins are accumulating, while XBP1, PERK and CHOP are the proteins that mediate the responses themselves. CHOP activates BAD protein, which is pro-apoptotic, and inhibits Bcl-2, which is anti-apoptotic.

ER overload response

If there is a protein accumulation in the ER or there is a viral infection, the will initiate a response called the ER overload response. This response will increase inflammation. It has three steps.

Ca2+ outflow from the ER
ROS formation
Activation of NF-κB

The overload response is involved in many diseases, like Alzheimer’s, cytic fibrosis and Marfan syndrome.

ER quality control

The ER has a mechanism to quality control all proteins it folds. If proteins are not folded correctly, and re-folding fails multiple times, the protein is degraded.

Diseases where the defect of ER is involved are called ER storage diseases. Cystic fibrosis is an ER storage disease. The CFTR itself is functional, but the ER quality control recognizes it as faulty, which causes the symptoms.

Prion diseases and Huntington’s disease are also ER storage diseases.