An unusual attribute of senescence-inducing factors

Specialized proteins (like cytokines and growth factors) clearly have a good side. They regulate cell growth, differentiation, and survival. Each protein has a specific isoelectric point (pI). This point is the pH (fluid acid or H+ level) at which the protein has no net charge.

Thus, a  basic protein (with lots of lysine and arginine amino acids) will have a high isoelectric point, as the pH at which the basic amino acids have no charge has to be much more basic. Conversely, an acidic protein has a low pI because it needs an acidic pH to have neutralization of the acidic (like glutamic and aspartic acid) amino acids.

Senescence-inducing cytokines (signaling proteins in the immune system) and growth factors tend to have an acidic pI. This suggests that the acidic charge of these proteins may contribute to their ability to induce senescence. For example, tumor necrosis factor-alpha (TNF-alpha) has an acidic pI of 5.8. TNF-alpha is a pro-inflammatory cytokine that has been shown to induce senescence in cells.

The table shows several examples of senescence-inducing cytokines. Note that all but one have an acidic pI (under 7.0). The one factor with a basic pI (Fas Ligand) has a 26 amino acid segment that is more acidic than basic; it is this segment that calls the shots for the Fas Ligand.

Let's look at the example of a senescence-inducing factor (that is not a protein) with an extremely low pI: lipopolysaccharide (LPS). This molecule is a major component of the outer membrane of Gram-negative bacteria. It is a potent endotoxin, which means that it can cause inflammation and other harmful effects when it enters the bloodstream. It has a pI of ~2.5.

LPS  was studied in lung alveolar cells (that line the airways). This pro-inflammatory factor induces senescence in cells and hinders tissue repair (5).

Senescence is a state of permanent cell cycle arrest that is characterized by a number of changes in gene expression and metabolism. Senescent cells can secrete harmful molecules that can damage other cells and tissues.

In this article I highlight an interesting observation: 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. 

1. Proteins of aging and their localization in the cell: 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 (this article): 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.