An international team led by researchers from Goethe University Frankfurt has discovered an intracellular sensor that monitors and controls the quality of MHC-I (Major Histocompatibility Complex class I) molecules. These molecules are crucial for immune surveillance, as they present protein fragments on the cell surface to help the immune system identify and destroy harmful cells, including cancer cells. This new sensor ensures that only functional MHC-I molecules reach the cell surface, while defective ones are retained and eventually degraded within the cell. Interestingly, a lack of this quality control mechanism can result in an increased number of MHC-I molecules on cancer cell surfaces, which may lead to an enhanced immune response against tumors.
This groundbreaking research, published in the journal Cell, sheds light on how cells use MHC-I molecules as a kind of “display” system to communicate their health status to immune cells. MHC-I molecules on the cell surface present protein fragments from within the cell, allowing the immune system to detect signs of infection, mutations, or other harmful changes. By showcasing these fragments, MHC-I molecules act as “radio masts” that broadcast internal cellular conditions to patrolling immune cells. When immune cells detect potentially dangerous protein fragments, they can target and destroy the compromised cell.
However, the effectiveness of this immune response hinges on the integrity of the MHC-I molecules themselves. If these molecules are defective, they may fail to accurately present cellular fragments, potentially allowing harmful cells to evade immune detection. To address this, the team has identified a previously unknown intracellular sensor that distinguishes between functional and defective MHC-I molecules, ensuring that only intact, operational MHC-I molecules are transported to the cell membrane.
Dr. Lina Herhaus, who conducted this research at Goethe University’s Institute of Biochemistry II before moving to the Helmholtz Centre for Infection Research, explained that the discovery of this sensor highlights a crucial mechanism within the immune system. “We’ve found that cells have a sensor that only allows functional MHC-I molecules to reach the plasma membrane, while defective ones are filtered out and broken down,” she stated.
This quality control mechanism is particularly essential because cells produce vast numbers of proteins to support their diverse functions, and errors are inevitable. Specialized receptors within the cell usually recognize these faulty proteins and route them to structures where they can be degraded. Through their study, the researchers identified a protein known as IRGQ as the key receptor responsible for ensuring the quality of MHC-I molecules.
The team experimented by using genetic interference to block the production of IRGQ in cells. Without IRGQ, defective MHC-I molecules accumulated and some were mistakenly incorporated into the cell membrane alongside functional molecules. Surprisingly, instead of weakening the immune response, the absence of IRGQ appeared to enhance it. Upon analyzing data from liver cancer patients, the researchers found that patients with lower levels of IRGQ had higher survival rates. This suggests that reduced IRGQ levels might actually amplify the immune system’s ability to recognize and attack cancer cells.
This observation was confirmed in a liver cancer mouse model. Mice without IRGQ showed a more aggressive immune response against liver tumor cells, and as a result, they had significantly longer survival times. According to Prof. Ivan Đikić from the Institute of Biochemistry II, who co-led the study with Dr. Herhaus, these findings indicate that IRGQ could be an important target for new liver cancer therapies. “By targeting IRGQ, we might enhance the immune system’s response against liver cancer cells,” Đikić explained. Given that liver cell carcinoma is the second deadliest form of cancer globally, these findings open up promising avenues for treatment.
The research team is now investigating whether IRGQ might influence other types of cancer in a similar way. Future therapies could involve developing drugs to target IRGQ and trigger its degradation, thereby allowing more MHC-I molecules to present fragments on cancer cell surfaces. This could help the immune system better recognize and attack cancer cells, potentially providing a new approach to treatment.
Beyond its implications for cancer therapy, this discovery also offers exciting potential for basic immunology research. Dr. Herhaus is eager to explore the broader role of IRGQ in immune function. She noted that understanding how IRGQ impacts the immune response during viral infections, for instance, could yield insights into the body’s overall defense mechanisms. “Our study raises a host of intriguing questions,” Herhaus said. “The answers could deepen our understanding of immune surveillance and potentially lead to broader applications in immunotherapy.”