In a groundbreaking study that elucidates critical early mechanisms of antiviral immunity, researchers at the Institute of Science Tokyo have unveiled how two pivotal proteins, LGP2 and MDA5, collaborate to detect and respond to viral RNA inside cells. Utilizing advanced structural and imaging technologies such as cryo-electron microscopy and high-speed atomic force microscopy, their investigation reveals the molecular choreography by which LGP2 binds to viral double-stranded RNA (dsRNA) and serves as a scaffold to recruit MDA5, facilitating the assembly of extensive filamentous complexes that ignite innate immune signaling.
The innate immune system serves as the essential frontline defense against viral invaders by recognizing molecular signatures distinct to viruses, such as dsRNA intermediates formed during viral replication cycles. MDA5, or melanoma differentiation-associated protein 5, is a well-characterized cytoplasmic sensor that detects long dsRNA molecules by polymerizing into filaments along the RNA strand. This filament formation is critical for activating downstream signaling pathways that culminate in the production of interferons and other antiviral molecules. However, MDA5’s efficiency diminishes when confronting shorter viral RNA fragments, posing challenges in viral recognition and response.
This limitation is addressed by the involvement of LGP2, the laboratory of genetics and physiology 2 protein, which binds viral RNA and translocates along it via an ATP-dependent mechanism. Unlike MDA5, LGP2 lacks intrinsic signaling capability but plays an instrumental auxiliary role. For years, the precise manner in which LGP2 modulates MDA5’s activity remained elusive. The current study, led by Associate Professor Kazuki Kato from Science Tokyo in collaboration with researchers from The University of Tokyo, sheds definitive light on this molecular interplay.
By integrating biochemical assays with high-resolution imaging, the team established that LGP2 preferentially targets the ends of dsRNA molecules, especially shorter RNA segments that are suboptimal substrates for MDA5 alone. Upon binding, LGP2 harnesses the energy derived from ATP hydrolysis to translocate along the RNA strand. In this dynamic process, LGP2 acts analogously to a leading bead threading through a string, effectively organizing and positioning MDA5 molecules as trailing beads that then polymerize into stable filaments. This scaffolding effect dramatically enhances filament nucleation on shorter RNA molecules.
Further analysis uncovered that the polymerization facilitated by LGP2 not only stabilizes individual MDA5 filaments but also promotes their lateral clustering. These small filament aggregates significantly potentiate the activation of mitochondrial antiviral signaling protein (MAVS), a crucial adaptor that amplifies antiviral signaling cascades inside the cell. The enhanced MAVS activation triggers robust production of interferons and other antiviral mediators, ultimately bolstering cellular defense mechanisms against viral replication and spread.
The implications of these findings extend deep into our molecular understanding of innate immunity. By demystifying the cooperative action of LGP2 and MDA5, this research fills a longstanding knowledge gap regarding how immune sensors effectively recognize varying lengths and forms of viral RNA. Moreover, the insights garnered here have potential translational applications. For instance, modulating LGP2 or MDA5 activity could provide novel therapeutic avenues for enhancing antiviral responses or controlling inflammation linked to aberrant immune activation.
This study also carries substantial promise for the rational design of RNA-based therapeutics and vaccines. Given the surge in mRNA vaccine technologies, understanding the nuanced mechanisms of RNA sensing may enable the development of formulations that maximize immune activation while minimizing adverse effects. As Professor Kato emphasizes, the elucidation of the LGP2-MDA5 partnership lays foundational knowledge that could inform the creation of safer and more efficacious RNA-delivery systems and immunomodulatory interventions.
The research was published on February 19, 2026, in the peer-reviewed journal Molecular Cell (Volume 86, Issue 4), evidencing meticulous experimental work including cryo-electron microscopy analyses that delineate protein structures at near-atomic resolution. This was complemented by high-speed atomic force microscopy, which provided vivid real-time visualization of protein dynamics along dsRNA substrates. Together, these methodologies furnished a comprehensive view linking structural conformation to functional outcome.
Supported by prominent funding agencies such as the Japan Agency for Medical Research and Development and the Japan Society for the Promotion of Science, the study exemplifies cutting-edge immunological research. The authors report no competing interests, underscoring the integrity and scientific rigor of their work. This advancement in understanding the molecular basis of viral RNA detection opens pathways for future exploration into other sensor protein interactions and their roles in innate immunity.
Institute of Science Tokyo, a newly established entity arising from the merger of Tokyo Medical and Dental University and Tokyo Institute of Technology, exemplifies interdisciplinary collaboration driving forward biomedical discovery. The convergence of expertise and state-of-the-art technologies at this institute was pivotal in achieving the insights detailed here, marking an important milestone in immunology research that resonates across basic science and clinical applications.
In sum, this landmark research articulates a detailed mechanism whereby LGP2 acts as both a sensor and architectural scaffold that nucleates MDA5 filament assembly on viral RNA, orchestrating a precise and potent antiviral signaling response. This revelation enriches the broader scientific narrative of host-virus interactions and sets the stage for innovative strategies to manipulate innate immune defenses for therapeutic benefit.
Subject of Research: Cells
Article Title: Molecular mechanism of MDA5 nucleation and filament formation by LGP2
News Publication Date: 19-Feb-2026
Web References: Molecular Cell Article
References:
Kato, K., Nureki, O., Kurihara, N., et al. Molecular mechanism of MDA5 nucleation and filament formation by LGP2. Molecular Cell. 2026; Volume 86, Issue 4. DOI: 10.1016/j.molcel.2025.12.019
Image Credits: Institute of Science Tokyo
Keywords
Innate immunity, viral RNA recognition, LGP2, MDA5, dsRNA, antiviral signaling, cryo-electron microscopy, atomic force microscopy, MAVS activation, RNA sensing, filament formation, mRNA vaccine development
Tags: antiviral signaling pathwayscryo-electron microscopy viral studydouble-stranded RNA recognitionearly antiviral immune signalingfilamentous complex formation in immunityhigh-speed atomic force microscopy imagingimmune system viral RNA detectioninnate immunity antiviral responseinterferon production mechanismLGP2 protein antiviral functionMDA5 viral RNA sensormolecular mechanisms of viral recognition
