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FLASH GENE
Symbol MYD88 contributors: mct/ - updated : 10-12-2015
HGNC name myeloid differentiation primary response gene (88)
HGNC id 7562
Corresponding disease
MYD88D MYD88 deficiency
Location 3p22.2      Physical location : 38.179.968 - 38.184.510
DNA
TYPE functioning gene
STRUCTURE 4.55 kb     5 Exon(s)
10 Kb 5' upstream gene genomic sequence study
text structure at least five exons
MAPPING cloned Y linked N status confirmed
Map pter - ENDOGL1 - ACVR2B - XYLB - SLC22A14 - SLC22A13 - OSR1 - MYD88 - ACAA1 - DLC1 - PLCD1 - VILL - CTDSPL - ITGA9 - cen
Physical map
LOC389106 3 LOC389106 LOC389107 3 similar to Hsp70/Hsp90 organizing protein homolog CG2720-PA LOC389108 3 LOC389108 LOC391527 3 similar to chromosome 2 open reading frame 7 EPM2AIP1 3p22.1 EPM2A (laforin) interacting protein 1 MLH1 3p21.3 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) LRRFIP2 3p24.3-p23 leucine rich repeat (in FLII) interacting protein 2 FLJ31715 3p22.1 hypothetical protein FLJ31715 GOLGA4 3p22-p21.3 golgi autoantigen, golgin subfamily a, 4 APRG1 3p22.1 AP20 region protein ITGA9 3p21.3 integrin, alpha 9 CTDSPL 3p21.3 CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small phosphatase-like VILL 3p21.3 CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small phosphatase-like PLCD1 3p21.3 phospholipase C, delta 1 DLEC1 ACAA1 3p23-p22 acetyl-Coenzyme A acyltransferase 1 (peroxisomal 3-oxoacyl-Coenzyme A thiolase) MYD88 3p22-p21.3 myeloid differentiation primary response gene (88) OSR1 3p22-p21.3 oxidative-stress responsive 1 SLC22A13 3p22-p21.3 solute carrier family 22 (organic cation transporter), member 13 SLC22A14 3p22-p21.3 solute carrier family 22 (organic cation transporter), member 14 XYLB 3p22-p21.3 xylulokinase homolog (H. influenzae) ACVR2B 3p22 activin A receptor, type IIB ENDOGL1 3p21.3 endonuclease G-like 1 LOC391528 3 similar to ribosomal protein L18a; 60S ribosomal protein L18a SCN5A 3p21 sodium channel, voltage-gated, type V, alpha (long QT syndrome 3) SCN10A 3p21-p22 sodium channel, voltage-gated, type X, alpha SCN11A 3p24-p21 sodium channel, voltage-gated, type XI, alpha KIAA1449 3p21.33 WD repeat endosomal protein GORASP1 3p22-p21.33 golgi reassembly stacking protein 1, 65kDa STI2 3p21.33 TPR domain containing STI2 AXUD1 3p22 AXIN1 up-regulated 1 CMYA1 3p21.33 cardiomyopathy associated 1 CX3CR1 3p21.32-p21.31 chemokine (C-X3-C motif) receptor 1 CCR8 3p21.32-p21.31 chemokine (C-C motif) receptor 8 hnRNPA1p 3p21.33 heterogeneous nuclear ribonucleoprotein A1 pseudogene
regionally located tightly linked to TLR9
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
4 - 2681 - 204 - 2013 2420429
5 - 2886 - 317 - 2013 2420429
  • MYD88L
  • activates innate immunity by transducing Toll-like receptor (TLR) signals
  • 4 - 2727 - 264 - 2013 2420429
    3 - 2546 - 159 - 2013 2420429
  • MYD88S
  • MYD88S mRNA levels are regulated by the SF3A and SF3B mRNA splicing complexes
  • 5 - 2862 34.6 309 - 2013 2420429
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouth   highly
     stomach   highly
    Lymphoid/Immunespleen   highly
     thymus   highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal death domain responsible for mediating interactions between MYD88 and members of the interleukin-1 receptor-associated kinase (IRAK) family
  • a DEATH domain
  • a TIR domain (a Toll/interleukin-1 receptor domain)
  • mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Myd88
    Homologene
    FAMILY
    CATEGORY adaptor , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • binding the cytoplasmic tail of TLR proteins leading to their activation and thus involved in innate immunity
  • initiating an intracellular signaling pathway leading to activation of NFKB and its target genes
  • adaptor or regulator in the IL-1R signaling pathway
  • involved in the response to CpG DNA (bacterial)
  • having the ability to activate the Ifna promoter in synergy with IRF-7 and TRAF6
  • involved in LPS-tolerant phenotype
  • signaling pathway of MYD88 downsteram of members of the TLR and IL1R family having a critical role in intestinal tumorigenesis
  • dispensable for the induction of IFN1 and the majority of antiviral cytokines
  • contributes to pancreatic beta-cell homeostasis in response to injury
  • with TIRAP, are adaptor molecules critically involved in the Toll-like receptor (TLR) 4 signaling pathway
  • induces the differentiation and maturation of dendritic cells not only by activating NF-kappaB and MAPK but also via suppressing MYC activity and expression
  • plays a critical role in reverse cholesterol transport, in part through promoting ATP-binding cassette A1 transporter upregulation
  • plays a key role in lipopolysaccharide-induced STAT3 activation in the hypothalamus
  • MYD88 pathway by LPS-mediated TLR4 activation induced the cell surface presentation of HSP90B1 through c-Jun N-terminal kinase (JNK)
  • TLR9–MyD88 activation leading to histone modification might be the signaling event responsible for the interaction between the malaria parasite P. falciparum and EBV gene expression in B cells contributing to the pathogenesis of endemic Burkitt lymphoma
  • mediator for the activation of NFE2L2
  • adaptor protein that mediates toll and interleukin IL1 receptor signalling
  • MYD88 and the associated kinases IRAK1 and IRAK4 are essential for activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) survival
  • MYD88 and IRAK1 are required to maintain the viability of ABC DLBCL cells
  • MYD88 is a critical mediator of Alu RNA-induced RPE degeneration
  • play an important role in T cells
  • unique role for the innate adaptor MYD88 in the regulation of Th17 cell differentiation
  • is a critical regulator of hematopoietic cell-mediated neuroprotection seen after stroke
  • essential adaptor protein for Toll-like receptors (TLRs)
  • MYD88 signalling is crucial during the development of the immune system but depending upon the ligand it may be dispensable at the time of the actual inflammatory challenge
  • mediates the optimal activation of the RAS/extracellular signal-regulated kinase (ERK) pathway by binding to ERK and protecting it from dephosphorylation
  • MYD88 relayed signals of TLR-induced IL1, which became dispensable for Th1 cell responses in the absence of T regulatory (Treg) cells
  • critical MYD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases
  • in pericytes, MYD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS immunity/defense
    PATHWAY
    metabolism
    signaling signal transduction
    host response against pathogens NF-kappa B signaling pathway, IL1 receptor and TLR signaling associating with the IL1 receptor complex
    a component
  • forms heterodimers with TIRAP
  • MYD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MYD88, 4 IRAK4 and 4 IRAK2 DDs
  • TLR9–MyD88 signaling axis is implicated in TLR9-induced suppression of EBV lytic gene expression
  • CD300A and CD300LF regulate the MYD88 and TICAM1-mediated TLR signalling pathways through differential activation of PTPN6 and PTPN11
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • associating with IL1R1, IL1R2, IL1RAP, IL18R1, IL18RAP, IRAK1, IRAK2
  • binding LBP, Toll-like receptors (TLR2, TLR4, TIRAP)
  • IL1, IL18
  • interaction with PTK2B, increased in macrophages, stimulated by LPS,and requiring the death domain of MYD88
  • interacting with FREM1 (potentiates MYD88 recruitment to control Ras-dependent amplification of NF-kappaB)
  • interaction with PRKD1 (PRKD1 is essential for MYD88-dependent proinflammatory immune responses)
  • interacting with LRRFIP2 and LRRFIP1, and both are positive regulators of NF-kappaB activity
  • triggers immunoglobulin class switching by activating B cells through the adaptor MYD88
  • TLR4 requires myeloid differentiation (LY96), and both TLR2 and TLR4 signal need myeloid differentiation factor (MYD88)
  • LRRFIP2 binds to MYD88 through its serine-rich domain (phosphorylation at serine 202 was found to regulate the dynamics of the LRRFIP2-MYD88 interaction, which in turn modulated the strength and duration of TLR4 signaling)
  • DEFB103B affects the activity of pro-inflammatory pathways associated with MYD88 and TICAM1
  • TBC1D23 likely acts downstream of the TLR-signaling adaptors MYD88 and TICAM2 and upstream of the transcription factor XBP1
  • DOCK8 functions as an adaptor in a TLR9-MYD88 signaling pathway in B cells
  • TICAM2 serves as the sorting adaptor for MYD88 in IL18 signaling, which then facilitates the signal transduction
  • IL10 activates TLR4 and requires MYD88 for cardiomyocyte survival
  • adaptor, linking TLR and IL1R1 to downstream signaling pathways in the innate immune system
  • MYD88-dependent IL23R expression contributes to IL17A production
  • MYD88 plays a critical role in integrating IL1A and IL23A signaling for Th17 cell proliferation and expansion
  • TIRAP and MYD88 are adaptor proteins for Toll-like receptors-2 and -4 (TLR2/4) which are engaged in transducing the signal to downstream molecules
  • ATG5, a key regulatory protein of autophagy, inhibits the formation of MYD88 condensed structures
  • PPP1CC is a positive regulator of MYD88-dependent proinflammatory innate immune activation
  • IRAK4 is recruited to the membrane-proximal adaptor MYD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NFKB1 activation
  • TICAM2 is required for the TLR2-dependent movement of MYD88 to endosomes following ligand engagement
  • TIRAP plays the crucial role of activating the MYD88-dependent pathway, which in turn controls the immune response (innate and adaptive) to Helicobacter pylori
  • cell & other
  • liposaccharide LPS
  • binding to bacterial cell-wall components
  • REGULATION
    induced by IL1
    Other TGF-beta1 facilitates ubiquitination and proteasomal degradation of MYD88 and thereby attenuates MYD88-dependent signaling
    regulated by MTA1 (involved in regulation of MYD88 which may constitute at least one of the mechanisms by which MTA1 stimulates LPS-induced NFkB signaling in stimulated macrophages)
    ASSOCIATED DISORDERS
    corresponding disease(s) MYD88D
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    of TLR4 and MYD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer
    tumoral somatic mutation     gain of function
    highly recurrent oncogenic mutations (MYD88 L265P), affecting MYD88 in activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) tumours
    Susceptibility
  • to pyogenic bacterial diseases
  • Waldenstrom macroglobulinemia (WM)
  • Variant & Polymorphism other
  • mutations associated with pyogenic bacterial diseases, including invasive pneumococcal diseases
  • high frequency of MYD88 L265P mutation in WM
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations
    diabete  
    inducible intestinal epithelial cell-specific deletion of MYD88 partially protects against diabetes and inflammation
    obesity  
    inducible intestinal epithelial cell-specific deletion of MYD88 partially protects against diet-induced obesity,
    obesity  
    targeting intestinal epithelial MYD88 constitutes a putative therapeutic target for obesity and related disorders
    ANIMAL & CELL MODELS
  • Myd88(-/-) mice produce no cytokine
  • mice with a targeted disruption of the Myd88 gene were unable to respond to IL1 nor to produce gamma-interferon and mediate natural killer cell activity in response to IL18
  • Myd88-deficient mice are highly susceptible, in terms of growth in blood and kidney and decreased survival, to infection with Staphylococcus aureus compared to wildtype mice
  • Apoe -/- Myd88 -/- double-null mice showed a marked reduction in early atherosclerosis
  • MyD88-deficient mice exhibited low serum and bone marrow concentration of Ifng compared with wild-type mice