IFIH1

Protein identityUniProt · HPA

UniProt accession

Q9BYX4

Gene

IFIH1

Ensembl

ENSG00000115267

Chromosome

2

Canonical length

1025 aa

Protein class

Disease related genes, Enzymes, Human disease related genes, Potential drug targets, Predicted intracellular proteins

Quaternary structure

Homodimer

OverviewNCBI Gene

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]

Canonical amino-acid sequenceUniProt

1025 residues, UniProt reviewed canonical sequence.

>Q9BYX4|IFIH1
     1  MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE
    61  LLLSTLEKGV WHLGWTREFV EALRRTGSPL AARYMNPELT DLPSPSFENA HDEYLQLLNL
   121  LQPTLVDKLL VRDVLDKCME EELLTIEDRN RIAAAENNGN ESGVRELLKR IVQKENWFSA
   181  FLNVLRQTGN NELVQELTGS DCSESNAEIE NLSQVDGPQV EEQLLSTTVQ PNLEKEVWGM
   241  ENNSSESSFA DSSVVSESDT SLAEGSVSCL DESLGHNSNM GSDSGTMGSD SDEENVAARA
   301  SPEPELQLRP YQMEVAQPAL EGKNIIICLP TGSGKTRVAV YIAKDHLDKK KKASEPGKVI
   361  VLVNKVLLVE QLFRKEFQPF LKKWYRVIGL SGDTQLKISF PEVVKSCDII ISTAQILENS
   421  LLNLENGEDA GVQLSDFSLI IIDECHHTNK EAVYNNIMRH YLMQKLKNNR LKKENKPVIP
   481  LPQILGLTAS PGVGGATKQA KAEEHILKLC ANLDAFTIKT VKENLDQLKN QIQEPCKKFA
   541  IADATREDPF KEKLLEIMTR IQTYCQMSPM SDFGTQPYEQ WAIQMEKKAA KEGNRKERVC
   601  AEHLRKYNEA LQINDTIRMI DAYTHLETFY NEEKDKKFAV IEDDSDEGGD DEYCDGDEDE
   661  DDLKKPLKLD ETDRFLMTLF FENNKMLKRL AENPEYENEK LTKLRNTIME QYTRTEESAR
   721  GIIFTKTRQS AYALSQWITE NEKFAEVGVK AHHLIGAGHS SEFKPMTQNE QKEVISKFRT
   781  GKINLLIATT VAEEGLDIKE CNIVIRYGLV TNEIAMVQAR GRARADESTY VLVAHSGSGV
   841  IEHETVNDFR EKMMYKAIHC VQNMKPEEYA HKILELQMQS IMEKKMKTKR NIAKHYKNNP
   901  SLITFLCKNC SVLACSGEDI HVIEKMHHVN MTPEFKELYI VRENKALQKK CADYQINGEI
   961  ICKCGQAWGT MMVHKGLDLP CLKIRNFVVV FKNNSTKKQY KKWVELPITF PNLDYSECCL
  1021  FSDED

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against IFIH1 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.31

Highest tissue expression

35 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about IFIH1.

Disease | AllUniProt

Conditions IFIH1 is implicated in, by any mechanism.

• Type 1 diabetes mellitus 19 (T1D19) MIM:610155
• Aicardi-Goutieres syndrome 7 (AGS7) MIM:615846
• Singleton-Merten syndrome 1 (SGMRT1) MIM:182250
• Immunodeficiency 95 (IMD95) MIM:619773

Disease | GeneticClinVar

42 pathogenic / likely-pathogenic of 1,753 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Aicardi-Goutieres syndrome 7
• Singleton-Merten syndrome 1
• Immunodeficiency 95
• IFIH1-related disorder
• 7 conditions

Disease | AutoantibodyPubMed

Conditions in which antibodies against IFIH1 are reported. Each links to that disease's full target list.

• Dermatomyositis 359
• Lung Diseases, Interstitial 268
• Myositis 77
• Polymyositis 21
• COVID-19 11
• Arthritis 5
• Arthritis, Rheumatoid 5
• Cytomegalovirus Infections 5
• Calcinosis 4
• Melanoma 4
• Thrombocytopenia 3

Showing 11 of 17 — disease pages carrying at least 10 antigens.

ReferencesPubMed · IEDB

Publications for IFIH1 from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

1.55

gnomAD pLI

0

gnomAD missense Z

-0.79

DepMap mean gene effect

-0.05

DepMap dependency class

none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 5% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• antiviral innate immune response
• cellular response to exogenous dsRNA
• cellular response to virus
• cytoplasmic pattern recognition receptor signaling pathway
• defense response to virus
• detection of virus
• innate immune response
• MDA-5 signaling pathway
• negative regulation of viral genome replication
• positive regulation of interferon-alpha production
• positive regulation of interferon-beta production
• positive regulation of interleukin-6 production
• positive regulation of response to cytokine stimulus
• positive regulation of tumor necrosis factor production
• protein complex oligomerization
• protein sumoylation
• regulation of type III interferon production
• response to virus
• type I interferon-mediated signaling pathway

Molecular functions

• ATP binding
• ATP hydrolysis activity
• DNA binding
• double-stranded RNA binding
• identical protein binding
• pattern recognition receptor activity
• protein domain specific binding
• ribonucleoprotein complex binding
• RNA binding
• RNA helicase activity
• single-stranded RNA binding
• zinc ion binding

Cellular components

• cytoplasm
• cytosol
• mitochondrion
• nucleus

Protein domainsUniProt · Pfam · InterPro

• Helicase, C-terminal domain-like
• Helicase/UvrB, N-terminal
• Death-like domain superfamily
• Helicase superfamily 1/2, ATP-binding domain
• RIG-I-like receptor, C-terminal regulatory domain
• P-loop containing nucleoside triphosphate hydrolase
• Caspase recruitment domain
• RIG-I-like receptor, C-terminal domain superfamily
• RIG-I-like receptor, C-terminal
• RIG-I-like Receptor (RLR) Helicase
• Helicase conserved C-terminal domain
• Type III restriction enzyme, res subunit
• C-terminal domain of RIG-I
• Caspase recruitment domain
• RIG-I receptor C-terminal domain

KeywordsUniProt

• Aicardi-Goutieres syndrome
• Antiviral defense
• ATP-binding
• Cytoplasm
• Diabetes mellitus
• Helicase
• Host-virus interaction
• Hydrolase
• Immunity
• Innate immunity
• Isopeptide bond
• Metal-binding
• Mitochondrion
• Nucleotide-binding
• Nucleus
• Phosphoprotein
• Repeat
• RNA-binding
• Ubl conjugation
• Zinc

InteractionsUniProt · HPA

Protein binding partners of IFIH1 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• ANKRD17
• ATG12
• ATG5
• DDX3X
• DDX60
• ECSIT
• IKBKE
• NLRC5
• NOD1
• PCBP2
• RNF123
• ZCCHC3
• TKFC
• MAVS