Ubiquitin, a Protein Complex Key to the Efficient Management of ER-phagy

Tuesday - August 1 2023, 00:07 UTC - 1 year ago

The endoplasmic reticulum is a complex network of tubes, sacs, and membrane-bound compartments responsible for maintaining cellular homeostasis and producing and regulating proteins, lipids, and hormones. A process called ER-phagy, facilitated by signal-receiving proteins, is responsible for ER breakdown. A recent study identified ubiquitin as the key player in driving ER-phagy and a malfunction of ER-phagy was identified as the underlying cause of a rare hereditary sensory and autonomic neuropathy.

The endoplasmic reticulum, often abbreviated as ER, is a complex network of tubes, sacs, and membrane-bound compartments that pervade the cells of humans, animals, plants, and fungi. It serves as the manufacturing hub for proteins, overseeing their production, ensuring they fold into the appropriate three-dimensional structure, and modifying them as needed. Additionally, the ER is integral to the production of lipids and hormones, and is responsible for maintaining the cell’s calcium balance.

In addition, the ER serves as the foundation for the cell’s transport system, facilitating the movement of materials within the cellular environment. It also plays a key role in quality control by directing misfolded proteins toward the cell’s internal waste disposal system. Furthermore, it neutralizes harmful toxins that find their way into the cell, thus safeguarding the cell’s functionality and health.

In view of its multiple tasks, the ER is constantly being remodeled. A process called ER-phagy (roughly "self-digestion of the ER") is responsible for ER degradation. Involved is a group of signal-receiving proteins – receptors – that are responsible for the membrane curvatures of the ER and thus for its multiple forms in the cell.

In ER-phagy, the receptors accumulate at specific sites on the ER and increase membrane curvature to such an extent that, as a consequence, part of the ER is strangulated and broken down into its component parts by cellular recycling structures (autophagosomes).

In cell culture experiments, biochemical and molecular biological studies, and computer simulations, the scientific team led by Professor Ivan Đikić of Goethe University Frankfurt first tested the membrane curvature receptor FAM134B and demonstrated that ubiquitin promotes and stabilizes the formation of clusters of FAM134B protein in the ER membrane.

Thus, ubiquitin drives ER-phagy. Đikić explains: "Ubiquitin causes the FAM134B clusters to become more stable and the ER to bulge out more at these sites. The stronger membrane curvature then leads to further stabilization of the clusters and, moreover, attracts additional membrane curvature proteins. So the effect of ubiquitin is self-reinforcing." The researchers were also able to detect cluster formation using super-high-resolution microscopy.

Đikić continues: "To fulfill this function, ubiquitin changes the shape of part of the FAM134B protein. This is another facet of ubiquitin that performs an almost unbelievable array of tasks to keep all different cell functions working." .

The importance of ER-phagy is demonstrated by diseases resulting from a defective FAM134B protein. A team led by Professor Christian Hübner from Jena University Hospital previously identified mutations in the FAM134B gene causing a very rare hereditary sensory and autonomic neuropathy (HSAN), in which sensory nerves die. As a result, patients are unable to perceive pain and temperature correctly, which can lead to incorrect stresses or injuries going unnoticed and developing into chronic wounds. In a long-standing collaboration between Jena University Hospital and Goethe University Frankfurt FAM134B was iidentified as a key regulator of ER-phagy.