MDA5, A Nucleic Acid Sensor Critical for Immune Response

RLR Family of Proteins

Melanoma differentiation-associated protein 5 (MDA5), also known as interferon-induced helicase-1 (IFH1), is one of the three members of the RIG-like receptors (RLRs) family of proteins. The RLR family of proteins share similar protein domains essential for their functions – namely the N-terminal caspase activation and recruit domains (CARDs), DExD/H box RNA helicase domain, and a C-terminal domain (CTD).

MDA5 is an RNA helicase that functions as a pattern recognition receptor (PRR) to recognize nucleic acids in the cytosol and initiate downstream inflammatory responses such as activating the type I interferon (IFN) signaling pathway and proinflammatory cytokines. Typically, MDA5 is present in low levels in resting cells, but upon activation by type 1 IFN, MDA5 expression is induced, creating a feed-forward loop in response to a virus infection¹.

Intracellular RNA Sensing and Interferon Signaling

RLRs such as MDA5 form an essential component of the innate immune response. RLRs function as a PRR which detects pathogen-associated molecular patterns (PAMPs) such as foreign viral nucleic acids. This event serves as the first line of defense. Upon recognizing and binding double-stranded RNA (dsRNA), the CARD domain of MDA5 binds to signaling adaptor MAVS. This leads to the activation of key immune regulator NFkB, which initiates IFN signaling cascade². Type I IFN signaling is essential in host defense against microbial infections; however, it also has to be well-regulated to avoid cytotoxicity caused by improper or prolonged IFN signaling³.

MDA5-Associated Pathologies

Because interferon signaling is integral to human antiviral immunity, it is no surprise that alterations to MDA5 are associated with specific inflammation-related pathologies. In fact, severe viral respiratory infections were observed in children with loss-of-function mutations in MDA5. These mutations result in MDA5 deficiency, therefore reducing inflammatory responses towards viral infections, leading to the abnormal increase in susceptibility to common respiratory RNA viruses⁴. Also, others have shown that gain-of-function mutations in MDA5 are associated with a spectrum of neuro-immunological phenotypes due to the enhanced interferon signaling⁵. One cause of a type 1 interferonopathy, known as Aicardi-Goutières syndrome (AGS), is caused by MDA5 mutations that resulted in elevated production of type I interferon⁶. AGS is a rare and severe disease characterized by numerous neurological symptoms such as seizures, hypotonia, spastic quadriplegia, etc.

MDA5 in Cancer

MDA5 has recently been implicated in cancer. Expressing MDA5 in cancer cells resulted in growth arrest and cell death. Similarly, overexpressing MDA5 in neuroblastoma cells resulted in less cell proliferation and more cell death. In several other cancers, MDA5 exhibited anti-cancer effects⁷. A ground-breaking study showed that cancer therapies such as DNA methyltransferase inhibitors trigger the activation of a viral defense mechanism by inducing the formation of dsRNA, which is caused by the upregulation of the IFN response via the activation of RNA sensors such as MDA5⁸. This results in anti-cancer effects such as reduced cell growth and apoptosis of tumor cells. Therefore, MDA5 has the potential to serve as an anti-cancer therapeutic. However, more studies will have to be performed to further explore the use of MDA5 in treating cancers.

References

1. Dixit, E. & Kagan, J. C. Chapter Four – Intracellular Pathogen Detection by RIG-I-Like Receptors. in Advances in Immunology (ed. Alt, F. W.) vol. 117 99–125 (Academic Press, 2013).
2. Kawasaki, T. & Kawai, T. Chapter One – Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System. in International Review of Cell and Molecular Biology (eds. Vanpouille-Box, C. & Galluzzi, L.) vol. 344 1–30 (Academic Press, 2019).
3. Chen, K., Liu, J. & Cao, X. Regulation of type I interferon signaling in immunity and inflammation: A comprehensive review. Journal of Autoimmunity 83, 1–11 (2017).
4. Asgari, S. et al. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. PNAS 114, 8342–8347 (2017).
5. Rice, G. I. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet 46, 503–509 (2014).
6. Oda, H. et al. Aicardi-Goutières Syndrome Is Caused by IFIH1 Mutations. Am J Hum Genet 95, 121–125 (2014).
7. Wu, Y., Wu, X., Wu, L., Wang, X. & Liu, Z. The anticancer functions of RIG-I-like receptors, RIG-I and MDA5, and their applications in cancer therapy. Transl Res 190, 51–60 (2017).
8. Chiappinelli, K. B. et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell 162, 974–986 (2015).