Overview of the Secretory Pathway - Molecular Cell …

Protein synthesis by membrane-bound and free ribosomes of secretory and non-secretory tissues

Section 17.3 Overview of the Secretory ..

Secretion is a major function of the endomembrane compartment. Most cells have scanty regions of ER, but in certain specialized secretory cells, the ER is abundant. The rough ER is highly developed in pancreatic acinar cells that secrete copious amounts of digestive enzymes () as well as in hepatocytes, the principal site of production of lipoprotein particles, which carry lipids via the bloodstream to other parts of the body. XBP-1(S) is a regulator of DGPCho synthesis and ER membrane development, and constitutive expression of XBP-1 is essential for the proper development of professional secretory cells, such as pancreatis islets () and hepatocytes ().

are inserted into the rough ER membrane during their synthesis; ..

Upon induction of the UPR, the mRNA encoding the X-box binding protein 1 (XBP-1) is spliced to form XBP-1(S), which encodes a transcription factor (). The site of splicing is at the ER membrane, where a transmembrane kinase/endonuclease called IRE1α modifies XBP1 transcripts upon accumulation of misfolded lumenal proteins. XBP-1(S) stimulates the expression of a host of genes, including those that encode the enzymes of the protein translational machinery and vesicular trafficking, and also stimulates membrane phospholipid synthesis (, ). The role of XBP-1(S) in initiating the program of membrane biogenesis was discovered in the context of the terminal differentiation of B lymphocytes into antibody-secreting plasma cells (). Stimulated lymphocytes greatly increase the size of the endomembrane compartment, which is accomplished by a program of lipid biosynthetic gene expression. Elevated gene expression, in turn, increases the abundance of membrane glycerophospholipid precursors that also allosterically activate the CCT ().

Although different lipids are synthesized in different organelles, they are widely distributed within the cell and the membrane composition of the different organelles does not necessarily reflect their lipid biosynthetic capacity. DGPCho is synthesized in the endomembrane compartment and in the nuclear compartment in immortalized cells, but it is present everywhere in the cell. DGPSer and CerPCho are synthesized in the ER and Golgi, but they are highly abundant in the plasma membrane. PlmePEtn is synthesized in the peroxisomes but does not accumulate as it is primarily secreted. Within the same membrane, lipids are transported to or segregated into one of the two leaflets of the membrane by virtue of their chemical structure or by the action of enzymes called flippases, whose function is to favor or force the movement of specific lipids between the two leaflets of the membrane (, ). The transport of lipids to different membranes can occur through the vesicular pathways, which allow the transport of membrane to even distant cellular locations or by lipid-transfer proteins, a process that is particularly active and fast within membrane contact sites (MCS), where membrane regions from different organelles come in close proximity (within 10 nm) to one another (). For example, the ER is known to generate MCS structures with mitochondria, plasma membrane, the Golgi apparatus, endosomes, and other organelles. The means by which DGPCho and DGPEtn are transported to the peroxisomes is still unknown, and MCS structures as well as vesicles may be responsible for mediating the process.

A secretory protein is any protein, ..

Protein homeostasis is maintained through a balance among protein synthesis, folding, assembly and degradation. The latter is crucial also to prevent accumulation of misfolded products in the cell. The conjugation to ubiquitin marks proteins for degradation by the proteasome. Secretory and membrane proteins are monitored for proper folding and oligomerisation in the endoplasmic reticulum (ER). In this compartment, defective proteins are recognised and targeted to the proteasome in a process called ER‐associated protein degradation or ERAD. A first step of retrotranslocation across the ER membrane to the cytosol is required. Ubiquitylation is carried out by ER enzymes and is also functionally intertwined with retrotranslocation. Malfunctioning of ERAD machinery or accumulation of folding‐defective proteins in the ER is associated with various human diseases ranging from neurodegenerative disorders to cancer. The design of drugs that meliorate ERAD or promote protein folding could provide new therapeutic strategies against these diseases.

Membrane phospholipid synthesis and endoplasmic …

The SRP receptor and the Sec61 proteins are ER membrane proteins – and there many other ER membrane, Golgi membrane and lysosome membrane proteins as well. In fact, even the (see ) of the cell membrane get processed in the secretory pathway. Many of these have several or tens of transmembrane domains (20-25 hydrophobic amino acids each) that have to be inserted in the correct order and orientation (for example, you really want your ion channels and transporters pointed in the right direction, into vs. out of the cell). Accordingly there are a bunch of fancy biological mechanisms for getting these proteins inserted into the membrane correctly. This is what the latter half of the above video depicts.