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 vs 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.

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

“…This initiates the formation of a MDA5 filament along the dsRNA, where multiple CARD domains assemble and recruit the signalling adaptor interferon promoter stimulator 1 (IPS1) (also denoted mitochondrial antiviral-signalling protein, MAVS). Activated IPS1/MAVS initiates the downstream signalling events leading to the activation of the transcription factors NF-κB and IRF-3, followed by the production of type I and III interferons (IFN)1234.…”

“…Type I and III IFNs have potent antiviral activities; they act in an auto- and paracrine manner to induce the expression of interferon-stimulated genes (ISGs) leading to an antiviral state in uninfected cells. They also promote innate and adaptive immune responses12345. Activation of type I and III IFN gene transcription is dependent on the activation of specific transcription factors, NF-κB and IRF-3.…”

Endogenous Retroelements and the Host Innate Immune Sensors

“…Can one specifically pull-down the active form of the receptor to distinguish between the agonist and nonagonist RNAs? While it is theoretically possible, transient, or dynamic nature of many of these interactions (del Toro Duany, Wu, & Hur, 2015; McKenna et al, 2007b) could make implementation of this idea technically challenging. Proving the activity of a bound RNA in physiological condition is also nontrivial as a wide range of RNAs can artificially activate these receptors when introduced in isolation or at high concentration.…”

Helicases in Antiviral Immunity: Dual Properties as Sensors and Effectors

“…Both RIG-I and MDA5 hydrolyze ATP only upon binding to dsRNAs but the impact of ATP hydrolysis differs, particularly in its effects on their oligomerization states. While MDA5 filament is formed independent of ATP, during ATP hydrolysis the MDA5 filament undergoes a disassembly from the filament termini, which leads to a decrease in the filament stability on short dsRNA and selective accumulation of MDA5 molecules on long dsRNA [28, 33, 34]. Since filament formation brings together CARDs for their oligomerization and this oligomerization of CARDs is required for activation of MAVS, the ATP-mediated negative regulation of MDA5 filaments explains how it avoids recognition of short cellular dsRNA (for more details, see review [34]).…”