Protein p62 puts the brakes on inflammation

In their efforts to learn to better understand and control the process of inflammation, those researchers recently discovered that a protein known as p62 acts as a “molecular brake” to keep inflammation in check and avoid collateral damage.

The implications of this finding are wide-ranging, notes Dr. Michael Karin, Distinguished Professor of Pharmacology and Pathology at the UCSD School of Medicine, who led the study—published in Cell—with Dr. Zhenyu Zhong, a postdoctoral researcher in his lab, and collaborators at Sanford Burnham Prebys Medical Discovery Institute. Among the other study authors were colleagues from Kyoto Prefectural University of Medicine and Cedars-Sinai Medical Center.

According to Karin, “In addition to explaining how our bodies can turn off inflammation when it’s no longer needed, these findings could have important implications for many age-related diseases.”

Macrophages play a major role in inflammation—they detect and swallow invading microbes and foreign particles. Activated macrophages release cytokines, small proteins that serve as signals to recruit and activate other immune cells for assistance. To produce and secrete one major inflammatory cytokine, interleukin-1beta (IL-1beta), macrophages employ molecular machines called inflammasomes. One of the most functionally diverse inflammasomes is the NLRP3 inflammasome, which releases IL-1beta when stimulated by toxins and microparticles such as silica, asbestos or cholesterol microcrystals.

One thing Karin and colleagues found was that foreign particles don’t act directly on the NLRP3 inflammasome, but instead damage the macrophage’s mitochondria. These damaged mitochondria then respond by releasing signals that activate the NLRP3 inflammasome and its production of IL-1beta.

In the short run, that’s beneficial for the body, but continuous production of IL-1beta can lead to an inflammatory chain reaction that results in multi-organ failure, septic shock and death.

And this is where p62 comes into the picture, because as Karin’s team discovered, to turn off IL-1beta production by NLRP3 inflammasomes, macrophages responding to foreign microbes and irritants also begin production of p62.

Zhong tells DDNews that p62 inhibits IL-1beta production, functioning as an autophagy adaptor that binds to damaged mitochondria, thereby promoting autophagic clearance of these mitochondria. Once these damaged mitochondria are removed, the NLRP3 inflammasome deactivates and IL-1beta production ceases.

The damaged mitochondria also activates Parkin—a protein that in humans is encoded by the PARK2 gene—which is required for p62 recruitment onto the damaged mitochondria. The Parkin ubiquitinates multiple mitochondrial outer membrane proteins. Then p62 is recruited to the damaged mitochondria by binding to these ubiquitinated mitochondrial proteins.

Thus, p62 functions as an adaptor that delivers the damaged mitochondria to autophagosome/lysosome, where they are eventually degraded, says Zhong, who continues: “We’ve suspected for quite some time that damage to mitochondria caused by either genetic or environmental factors is the root cause of many age-related diseases, all of which are associated with chronic, low-grade inflammation. Therefore, p62—and its part in eliminating damaged mitochondria—could provide a new target for preventing such diseases. We already know that Parkin plays a role in a rare form of Parkinson’s disease.”

“In terms of therapeutic potential, we think that drugs that could increase the mitophagy/autophagy pathway (in which p62 and Parkin play critical roles) would be beneficial for a number of human inflammatory diseases, such as gout, atherosclerosis, type 2 diabetes, macular degeneration, Alzheimer’s disease and cancers, because these disorders are all associated with hyper-activation of the NLRP3 inflammasome,” adds Zhong. “Testing the effect of autophagy-enhancing drugs would be a good direction to go in the future.”