IFIH1

Official Full Name

interferon induced with helicase C domain 1

Organism

Homo sapiens

Gene ID

64135

Background

IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]

Synonyms

AGS7; Hlcd; MDA5; IMD95; MDA-5; RLR-2; IDDM19; SGMRT1

Cat.No.	Product Name	Price
CSC-DC007425	Panoply™ Human IFIH1 Knockdown Stable Cell Line	Inquiry
CSC-SC007425	Panoply™ Human IFIH1 Over-expressing Stable Cell Line	Inquiry
CSC-RT2138	Human IFIH1 Knockout Cell Line-A549	Inquiry

Cat.No.	Product Name	Price
AD07897Z	Human IFIH1 adenoviral particles	Inquiry
LV15182L	human IFIH1 (NM_022168) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH316893	shRNA set against Human IFIH1 (NM_022168.3)	Inquiry
SHH316897	shRNA set against Mouse IFIH1 (NM_027835.3)	Inquiry
SHW003065	shRNA set against Chicken IFIH1 (NM_001193638)	Inquiry

Cat.No.	Product Name	Price
CDCS415474	Human IFIH1 ORF Clone (BC046208)	Inquiry
CDFL006032	Mouse Ifih1 cDNA Clone(NM_027835.3)	Inquiry
CDFR008739	Rat Ifih1 cDNA Clone(NM_001109199.1)	Inquiry
MiUTR3H-08852	IFIH1 miRNA 3'UTR clone	Inquiry
CDCB158208	Human IFIH1 ORF clone (BC046208)	Inquiry
CDCB164540	Chicken IFIH1 ORF Clone (NM_001193638)	Inquiry
CDCB191588	Rabbit IFIH1 ORF clone (XM_002712221.2)	Inquiry
CDCL119417	Human Ifih1 ORF clone (NM_001164477.1)	Inquiry
CDCR260454	Mouse Ifih1 ORF Clone(NM_027835.3)	Inquiry
CDCR375826	Rat Ifih1 ORF Clone(NM_001109199.1)	Inquiry
CDCS415475	Human IFIH1 ORF Clone (BC111750)	Inquiry

Detailed Information

The IFIH1 gene encodes melanoma differentiation-associated protein 5 (MDA5), a cytoplasmic pattern recognition receptor belonging to the RIG-I-like receptor family with a DExD/H-box helicase domain. MDA5 functions as a critical viral RNA sensor, structurally composed of: (1) a DExD/H-box helicase core that recognizes viral RNA, (2) two tandem caspase activation and recruitment domains (CARDs) that are released upon ligand binding to activate downstream signaling, and (3) a C-terminal domain that interacts specifically with the mitochondrial antiviral signaling protein (MAVS). IFIH1 transcription and protein expression are strongly induced by type I interferons, forming a positive feedback loop that primes cells for rapid antiviral responses. These structural features and inducible expression patterns establish MDA5 as a central player in innate immunity.

Biological Significance

MDA5 serves as a sentinel of the innate immune system, specifically recognizing long double-stranded RNA (dsRNA) in the cytoplasm. Unlike RIG-I, which preferentially senses short dsRNA or 5'-triphosphorylated RNA, MDA5 exhibits higher affinity for long dsRNA (>1 kb), typical replication intermediates of many viruses, including picornaviruses. MDA5 can also detect viral RNA lacking 2'-O-methylation of the 5' cap, a common viral evasion strategy. Upon binding RNA ligands, MDA5 undergoes a conformational change, exposing the CARD domains and forming prion-like aggregates on the mitochondrial outer membrane via CARD–CARD interactions with MAVS. This platform recruits and activates TBK1 and IKKε kinases, which phosphorylate IRF3 and IRF7, leading to the transcription of type I interferons (IFNs) and interferon-stimulated genes (ISGs). The resulting antiviral state inhibits viral entry, replication, assembly, and release.

Figure 1. Model of viral dsRNA recognition and MDA5 signaling pathway resulting in expression of type I and III interferons. (Looney BM, et al., 2015)

Beyond RNA viruses, MDA5 can detect certain DNA viruses, such as vaccinia virus, likely by sensing RNA intermediates transcribed by cellular RNA polymerase III from viral DNA. Thus, MDA5 constitutes a critical first line of defense against diverse viral infections.

Clinical Significance

IFIH1/MDA5 has a dual clinical significance:

Loss-of-function: Increases susceptibility to viral infections. Genome-wide association studies (GWAS) show that IFIH1 polymorphisms reducing MDA5 activity are associated with lower risk of type I diabetes and some autoimmune diseases, likely by decreasing inappropriate recognition of self-RNA. However, such variants increase susceptibility to certain viruses, particularly enteroviruses.

Gain-of-function: Causes rare autoinflammatory syndromes. Gain-of-function IFIH1 mutations underlie disorders such as Aicardi-Goutières syndrome and Singleton-Merten syndrome, where MDA5 becomes constitutively active, triggering chronic type I IFN responses even in the absence of viral RNA. Patients present with severe neurological defects, skin manifestations, and autoimmunity. Abnormal MDA5 activation is also implicated in systemic lupus erythematosus and dermatomyositis, particularly in MDA5-antibody-positive dermatomyositis, which correlates with rapidly progressive interstitial lung disease and poor prognosis.

In antiviral immunity, MDA5 detects critical human pathogens including rhinoviruses, coronaviruses, and dengue virus. For example, during SARS-CoV-2 infection, MDA5 triggers early type I IFN responses, though viruses have evolved mechanisms to evade its detection.

Therapeutically, targeted inhibition of MDA5 or its downstream pathways offers a promising approach for treating autoinflammatory diseases caused by excessive MDA5 activity. Conversely, MDA5 agonists or ligand mimetics could serve as adjuvants to enhance early antiviral immunity.

References

Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441(7089):101–105. doi:10.1038/nature04734
Oda H, Nakagawa K, Abe J, et al. Aicardi-Goutières syndrome is caused by IFIH1 mutations. Am J Hum Genet. 2014;95(1):121–125. doi:10.1016/j.ajhg.2014.06.007
Pichlmair A, Schulz O, Tan CP, et al. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol. 2009;83(20):10761–10769. doi:10.1128/JVI.00770-09
Looney BM, Xia CQ, Concannon P, et al. Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression. Curr Diab Rep. 2015 Nov;15(11):96.

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