Proteins of aging and their localization in the cell

Our human body has 20,000 genes that produce different types of proteins (each protein is further modified giving rise to multiple variations for any given protein (1). As the protein is produced in the rough endoplasmic reticulum, it is then packaged in rounded structures (vesicles) that make their way to the Golgi apparatus. From there proteins are distributed to different cellular subdivisions. 

Basolateral segregation of proteins

Cells show specialization by having a top and a bottom orientation. Thus, neurons have a cell body and an axon; intestinal cells have a basolateral membrane and an apical membrane that faces the lumen; gland cells also have a basolateral membrane and an apical membrane that faces the inside of the gland.

In the image above, one can see elongated epithelial cells seemingly stuck together with the nucleus sitting very close to the basal membrane. If you click on the image, you can see the very fine "brush border" on the apical membrane.

The apical or "top" membrane of the cell is typically very different from the  basolateral or "bottom" membrane. Each section has its own function within the cell and displays a different set of membrane proteins. Thus, specialization happens as the cell segregates different types of proteins to different parts of the cell.

Dysfunctional expression or activation of certain proteins can lead to cell senescence. These "proteins of aging" tend to segregate to the basolateral membranes of the cell.

Here are 5 proteins that preferentially localize to the basolateral membranes of the cell. 

• Epidermal Growth Factor Receptor (EGFR) (2, 3, 4)
• Transforming Growth Factor beta receptor (5, 6, 7, 8)
• Monocyte chemoattractant protein-1(MCP-1) (9, 10, 11)
• Interleukin 6 Receptor (12, 13, 14)
• Receptor for Advanced Glycation Endproducts (RAGE) (15, 16)

What is fascinating is that some of those proteins (for example, EGFR) are important in healthy cellular growth and proliferation. However, the cell is propelled down a senescent path when those proteins are dysfunctionally activated. 

Unfortunately, senescent cells often exhibit a senescence-associated secretory phenotype (SASP), characterized by the secretion of various pro-inflammatory factors. And those same factors promote senescence in nearby healthy cells.

It's not good. This is why many therapies look at blocking those membrane proteins, as demonstrated in the table above. 

As you can imagine, there are two sides to the coin. EGFR proteins are related to cancer cell growth. Thus, blocking EGFR proteins (for example, with Herceptin) also induces cancer cell senescence (17).

1. Proteins of aging and their localization in the cell (this article): Dysfunctional or hyper-functional membrane proteins that induce aging often reside in the basolateral regions of the cellular membrane.
2. Why it is important to learn about Senescence-associated secretory phenotype (SASP) proteins: Senescent cells accumulate over time and contribute to age-related diseases. They do this primarily by secreting Senescence-associated Secretory Phenotype (SASP) proteins. 
3. Senescent cells display unhealthy acidification of the cytoplasm: There are multiple pathways all cascading to generate increased in cytoplasmic acid. These create a positive feedback loop that sets the cell up for a vicious cycle of dysfunctional intracellular organelles and ongoing  intracellular acidosis.
4. An unusual attribute of senescence-inducing factors: Pro-inflammatory factors tend to have more acidic isoelectric point, with more acidic side groups. The evidence suggests that there is a correlation between acidic side-groups, isoelectric point, and senescence-inducing factors.