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ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly

Xiao-Peng Han1, Ming Rao1, Yu Chang2,3,4

  • 1State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Cell Research
|September 20, 2025
PubMed

Insights

MDA5, a key immune sensor, moves along viral dsRNA like a motor. Its regulated movement and interaction with LGP2 are crucial for initiating immune responses and maintaining homeostasis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • MDA5 (Melanoma Differentiation-Associated gene 5) is a RIG-I-like receptor crucial for innate immunity.
  • MDA5 activation involves filament formation along viral double-stranded RNA (dsRNA).
  • The ATPase activity of MDA5 is essential for immune homeostasis but its mechanism is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of MDA5 activation and its role in immune homeostasis.
  • To investigate the role of MDA5 ATPase activity in filament formation.
  • To understand the regulatory function of LGP2 in MDA5 signaling.

Main Methods:

  • Biophysical assays to study MDA5 translocation along dsRNA.
  • Biochemical experiments to analyze MDA5-dsRNA interactions.
  • In vitro reconstitution assays to investigate MDA5 filament formation.

Main Results:

  • MDA5 functions as an ATP-hydrolysis-driven motor translocating unidimensionally (1D) along dsRNA.
  • Cooperative loading of multiple MDA5 motors onto dsRNA occurs, but their movements are often unsynchronized.
  • LGP2 binds to MDA5 motors, inhibiting their movement and promoting filament assembly via a translocation-directed mechanism.

Conclusions:

  • MDA5 utilizes 1D translocation as a unique strategy for higher-order protein oligomerization.
  • This mechanism reveals a novel pathway for regulating innate immune responses.
  • The findings provide new insights into maintaining immune homeostasis through controlled MDA5 activation.

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