Molecular Dissection of Aggresophagy: Identification of a Central Enzyme Regulating Aggresome Clearance

When the cell’s first line of defense—the ubiquitin-proteasome system (UPS) is unable to break down damaged or misfolded proteins, the cell needs a backup plan. In such cases, misfolded proteins are collected into a centralized location in the cell called the microtubule-organizing center (MTOC). These collections are called aggresomes.

Forming aggresomes helps protect the rest of the cell from the toxic effects of protein aggregates. However, aggresomes are not a permanent solution they must be cleared to prevent long-term damage.

To clear them, the cell uses a process called aggrephagy a form of autophagy that specifically targets aggresomes for degradation.

Autophagy is a process cells use to break down and recycle components, including damaged organelles, protein aggregates, and even invading bacteria. During autophagy, cellular material is enclosed within a membrane, forming a structure called an autophagosome, which then fuses with a lysosome where the contents are broken down and recycled.

Aggrephagy is a type of selective autophagy. It specifically targets protein aggregates, including aggresomes. For this to happen, several things must occur:

1. The cell must identify which proteins or aggregates need to be removed.
2. The aggresomes must be moved to the right location.
3. Specialized receptors must recruit autophagy machinery to form autophagosomes.
4. These autophagosomes must fuse with lysosomes to allow for degradation.

Until recently, scientists didn’t fully understand what triggered this entire process or which molecules were essential for getting it started. That’s where this new discovery comes in.

Researchers have now identified a specific enzyme that plays a central role in aggresophagy. While the exact name of the enzyme can vary depending on the study (for example, some studies focus on HDAC6, USP10, or TRIM50), the general finding is that this enzyme performs several essential tasks:

• It recognizes ubiquitinated proteins, meaning proteins that have been tagged for removal.
• It helps transport aggresomes to the perinuclear region of the cell.
• It helps recruit autophagy receptor proteins such as p62/SQSTM1, which are required to link the aggresome to the autophagic machinery.
• It works with proteins like LC3 to help form the autophagosome membrane around the aggresome.

If the enzyme is not working properly or if its levels are too low cells are much less efficient at clearing aggresomes. This can result in a buildup of toxic proteins, leading to cell stress, dysfunction, and even death.

Protein aggregation and failure to clear these aggregates are seen in many neurodegenerative diseases, such as:

• Alzheimer’s disease
• Parkinson’s disease
• Huntington’s disease
• Amyotrophic lateral sclerosis (ALS)

In these conditions, misfolded proteins form clumps in nerve cells and disrupt their function. If scientists can better understand the enzymes that help cells remove these clumps, they can look for ways to enhance or support this natural process. This could reduce cell stress and improve cell survival.

Beyond neurological conditions, improving aggresophagy might help in other diseases where cellular stress plays a role, including some types of cancer and inflammatory diseases.

Now that this enzyme has been identified, scientists are exploring several important questions:

• Can its activity be safely increased in cells that are under stress?
• How is this enzyme regulated under normal conditions and in disease?
• Are there natural molecules in the body that influence this enzyme’s function?
• Can supporting this pathway help slow down or prevent protein aggregation diseases?

Research is also continuing in model systems such as yeast, mice, and cultured human cells to understand how this enzyme works in different biological contexts.