15.3:
Role of ER in the Secretory Pathway
A specific signal sequence directs polypeptides to the ER.
While some of these proteins remain as permanent ER residents, others are sorted in the ER lumen before being transferred to their final destination via the secretory pathway.
The proteins that enter the ER lumen are called soluble proteins.
They undergo appropriate folding, modifications, and quality checks in the ER lumen before being packaged into membrane-enclosed vesicles.
These vesicles carry soluble proteins, such as hormones and enzymes, for intracellular distribution to other organelles of the endomembrane system like lysosomes or for secretion into the extracellular environment.
Unlike soluble proteins, the integral membrane proteins do not completely translocate into the ER lumen. They simply embed their hydrophobic domains into the ER membrane.
The orientation of such transmembrane proteins is secured at the ER membrane and maintained throughout the vesicular transport until they reach their destination, where they form surface receptors or transporters.
15.3:
Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved in the secretory pathway are the endoplasmic reticulum, the ER-Golgi intermediate compartment, and the Golgi apparatus. Eventually, the functional protein cargo is delivered within the endomembrane system, exported out of the cell, or inserted into the plasma membrane.
Endoplasmic reticulum: the gateway to the secretory pathway
The endoplasmic reticulum is the primary gateway to the secretory pathway. It is the site where the proteins are folded, modified, and checked for quality before entering the secretory pathway. Various physiological stresses can increase the demand for secretory proteins or cause the accumulation of misfolded proteins in the ER. The disruption in the balance between protein demand and capacity to deliver correctly folded proteins in the ER causes stress.
Unchecked ER stress disturbs ER homeostasis, resulting in cellular dysfunction and disease. The primary characteristics of ER-related diseases are decreased protein folding capacity, failure to recognize and respond to misfolded proteins, and improper activation of responses to misfolded proteins. ER stress is implicated in the pathogenesis of diseases like diabetes mellitus, viral infections, and cancer. For example, in type II diabetes mellitus, insulin resistance in the peripheral tissues of the liver results in hypersecretion of insulin by the β cells. The secretory overload experienced by the β cells skews the ER balance. It can also result in cell death in later stages of type II diabetes mellitus.
Suggested Reading
- Lin, Jonathan H., Peter Walter, and TS Benedict Yen. "Endoplasmic reticulum stress in disease pathogenesis." Annu. Rev. Pathol. Mech. Dis. 3 (2008): 399-425.