Frontline Of Virus Detection Inside Human Body

When a virus enters the body, our body quickly detects it and begins to respond. This first line of defense is known as innate immunity.

In contrast, what many people imagine when they hear the word "immunity"-such as vaccines or antibodies-refers to a later system called adaptive immunity, which acts after the initial response. Innate immunity works like an early warning system, rapidly sensing the invasion of viruses.

A key player in innate immunity is a protein called MDA5, which detects viral RNA and alerts the body to the presence of an invader. It was already known that another protein, LGP2, helps MDA5 function effectively.

However, researchers have long faced a fundamental question: How exactly does LGP2 assist MDA5? While experiments had shown that LGP2 binds to RNA and enhances MDA5 activity, the details of how and where this binding occurs remained unclear. Different studies reported conflicting results, making this a long-standing debate in the field.

To address this question, a research team led by Tenure-track Associate Professor Kazuki Kato at Institute of Science Tokyo (Science Tokyo) used advanced techniques including cryo-electron microscopy, which allows detailed visualization of molecular structures, and high-speed atomic force microscopy, which captures molecular movements in real time.

The study revealed that LGP2 does not act through a single step, but rather functions through a sequence of coordinated actions.

First, LGP2 binds to the end of viral RNA. It then uses energy from ATP to move from the end toward the interior of the RNA. At these sites, LGP2 creates a platform that allows MDA5 molecules to gather efficiently.

This mechanism enables MDA5, which typically responds only to long RNA molecules, to also detect shorter RNA fragments. Moreover, the resulting structures gather into clusters called microclusters, which amplify the immune response.

Previously, scientists debated whether LGP2 binds to the ends or the internal regions of RNA. This study resolves that long-standing debate by showing that both are correct-LGP2 first binds to the end and then moves inward, forming a continuous process.

During viral infection, many short RNA fragments are produced. Until now, these fragments were thought to be easily missed by the immune system.

This study shows that, with the help of LGP2, even these short RNA molecules can be efficiently recognized. This finding may contribute to the development of new treatments and preventive strategies against a wide range of RNA viruses, including influenza and measles.

It may also provide new insights into inflammatory and autoimmune diseases caused by excessive immune responses.

MDA5 and LGP2 play important roles in immune responses to various viral infections. The next time you catch a cold, try imagining LGP2 moving along viral RNA, helping MDA5 gather and trigger your body's defense system.

(Kazuki Kato, Tenure-track Associate Professor, Mechanistic Immunology Research Unit, Institute of Integrated Research, Institute of Science Tokyo)

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