MDA5-filament, dynamics and disease

Abstract

Melanoma Differentiation-Associated gene 5 (MDA5), encoded by the gene IFIH1, is a cytoplasmic sensor for viral double-stranded RNAs (dsRNAs). MDA5 activates the type I interferon signaling pathway upon detection of long viral dsRNA generated during replication of picornaviruses. Studies have shown that MDA5 forms a filament along the length of dsRNA and utilizes ATP-dependent filament dynamics to discriminate between self versus non-self on the basis of dsRNA length. This review summarizes our current understanding of how the MDA5 filament assembles and disassembles, how this filament dynamics are utilized in dsRNA length-dependent signaling, and how dysregulated filament dynamics lead to pathogenesis of immune disorders.

Fig 1

Schematic of viral RNA recognition and signal activation by RIG-I and MDA5. These receptors recognize distinct groups of viral RNAs but activate the IFNα/β signaling pathway through the common adaptor molecule, MAVS.

Fig 2

Model of MDA5 filament formation and signal activation. MDA5 contains the 2CARD, helicase domain and CTD. Upon dsRNA binding, helicase-CTD forms a ring-like structure, which cooperatively stacks along dsRNA to assemble into a filament. Filament formation brings together neighboring 2CARDs into proximity and induces oligomerization of 2CARD alongside the filament. The 2CARD oligomer then triggers monomer-to-filament transition of MAVS and activates the downstream IFN signaling pathway.

Fig 3

Kinetic model for dsRNA length discrimination by the MDA5 filament. (A) ATP hydrolysis promotes end-disassembly of the MDA5 filament, which results in dsRNA length-dependent stability. (B) Multi-nucleated filament repairs gaps (or discontinuity) during ATP-mediated filament rearrangement. During dynamic equilibrium between assembly and ATP-driven end disassembly reactions, short filaments disassemble faster than longer ones, allowing continued elongation of longer filaments to more accurately reflect the length of underlying dsRNA scaffolds. (C) The role of slow nucleation kinetics in dsRNA length discrimination by MDA5. On short dsRNA, RNA binding occurs primarily by rate-limiting nucleation, whereas on long dsRNA, it is mediated by rapid filament elongation. Thus, slow nucleation selectively suppresses MDA5 binding to short dsRNA.

Fig 4

Model of how the gain-of-function (GOF) mutations in MDA5 cause Aicardi-Goutieres Syndrome (AGS). These mis-sense mutations over-stabilize the MDA5 filament, resulting in increased sensitivity to short dsRNAs and aberrant activation by as-yet-unidentified cellular RNAs.