Biomedical Updates

Halting Unfolded Protein Response

Recent research conducted at the School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, has shown that proteins requiring post-translational modifications such as N-linked glycosylation—important for the folding of some proteins—are processed in the endoplasmic reticulum (ER), the membrane network organelle structure within cells (see Fig. 1).1 Cellular stresses can lead to dysfunction of the ER and ultimately to an imbalance between protein-folding capacity and protein-folding load. This can help cause what are known as “conformational diseases,” diseases that are associated with improperly folded proteins, including cancer, cystic fibrosis, emphysema, liver disease, prion disease (such as mad cow), even chronic pain (opioid receptors misfolded in the ER) and possibly cataracts.

Within cells, there is a monitor system for protein folding, an inbuilt quality control system involving both the ER and the apparatus of what are called Golgi organelles. Unfolded or misfolded proteins are tagged for degradation or sent back through the folding cycle to determine if they can be corrected. However, when too many misfolded proteins are accumulated, they can also trigger what is known as unfolded protein response (UPR). This complex signaling program performs three functions: adaptation, alarm, and apoptosis.

Magnus Manske

Fig. 1 Endoplasmic reticulum (ER) The ER serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins in sacs called cisternae. 1. Nucleus, 2. Nuclear pore, 3. Rough endoplasmic reticulum (RER), 4. Smooth endoplasmic reticulum (SER), 5. Ribosome on the rough ER, 6. Proteins that are transported, 7. Transport vesicle, 8. Golgi apparatus, 9. Cis face of the Golgi apparatus, 10. Trans face of the Golgi apparatus, 11. Cisternae of the Golgi apparatus.
During adaptation, the UPR attempts to reestablish folding homeostasis by inducing chaperones that enhance protein folding to act. At the same time, mechanisms operates to reduce ER folding load while the degradation rate of unfolded proteins is increased.

If these steps fail to halt the accumulated damage, the UPR triggers a cellular alarm and a mitochondrial mediated apoptosis program. However, UPR rescue mechanisms do not always work and the consequences of these malfunctions are associated with a wide variety of disease states including tumor progression and diabetes, along with immune and inflammatory disorders.

Fortunately, as the Cornell researchers point out, UPR is a complex signaling program mediated by three ER transmembrane receptors, one of which requires the osmolyte inositol to function properly. It is good to know that there are other osmolytes which can be of benefit to help prevent the dilemma of misfolded proteins. Among these are betaine, creatine, glycine, taurine, trehalose, and beta-alanine, each of which is naturally found in living tissue in substantial quantities, is readily available, has been used safely in relatively large amounts as supplements or as components of foods for long periods of time, and is reasonably inexpensive.


  1. Chakrabarti A, Chen AW, Varner JD. A review of the mammalian unfolded protein response. Biotechnol Bioeng 2011 Aug 1. doi: 10.1002/bit.23282. [Epub ahead of print]

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