MAPK, p62, autophagy and inflammation

I was reading papers about proteasomal degradation and autophagy and one study has demonstrated that inhibition of autophagy was sufficient to trigger “we have inflammation” program in the cells.

This inhibition was done by p38 MAPK protein, which inhibits ULK1 - a protein that controls initiation of autophagy. Inhibition of ULK1 was sufficient to start “inflammation” without actual trigger of inflammation.

Next, another review described that inhibition of autophagy results in accumulation of p62 protein (Sequestosome 1) and this accumulation has a wide cascade of consequences: at first it activates Nrf2 in a vicious cycle (Nrf2 activated leads to production of more p62), p62 prevents assembly of GABA-A receptors, proteasomal machinery becomes overloaded, the cells now have internal stress that feeds itself.

H2O2 was also mentioned to inhibit proteasomal degradation, which also leads to accumulation of p62 which has to be cleared by autophagy (if it works still), same consequences as in the case of inhibited autophagy.

What triggers MAPK? Many things, LPS is among them.

Which means any infection or stimulation of normal immune response in the body that already has reduced capacity to clear proteins (either because autophagy is not worker well or proteasomal degradation is impaired) has a chance to throw the cells into never resolving inflammation.

Quotes

We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)–dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia (R1)

Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. (R1)

Defective autophagy leads to p62 accumulation, and p62 levels are used as a marker for autophagic flux, along with LC3B (R2)

Notably, p62 interacts with Keap1 (Figure 1A), which prevents its inhibitory binding to Nrf2. Increased p62 leads to hyperactivation of Nrf2 target genes, which protect against oxidative damage and inflammation. The interaction between p62 and Keap1 declines with age and is lost in some neurodegenerative diseases, leading to age-associated oxidative damage and inflammation.

Further adding to this decline is the oxidative damage to the p62 promoter, demonstrated in cells treated with H2O2, which yields lower p62 levels.

Another recent finding shows that treatment with spermidine, a lifespan-extending polyamine, upregulates p62 expression, and this induces cytoprotective autophagy of female germline stem cells (FGSCs) ex vivo. The upregulation of p62 by spermidine is indispensable to delay aging caused by oxidative stress-induced senescence. (R2)