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FLASH GENE
Symbol ERN1 contributors: mct - updated : 09-10-2014
HGNC name endoplasmic reticulum to nucleus signaling 1
HGNC id 3449
Location 17q23.3      Physical location : 62.120.389 - 62.207.502
Synonym name
  • inositol-requiring 1
  • protein kinase/endoribonuclease
  • ER to nucleus signaling 1
  • Synonym symbol(s) IRE1, IRE1P, FLJ30999, MGC163277, MGC163279, IRE1alpha, IRE1a
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 87.11 kb     22 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    HAN11 17q24.2 WD-repeat protein LOC51204 17q24.2 clone HQ0477 PRO0477p LOC390806 17 similar to Hypothetical protein FLJ14668 MAP3K3 17q24.2 mitogen-activated protein kinase kinase kinase 3 MGC10986 17q24.2 hypothetical protein MGC10986 LYK5 17q24.2 protein kinase LYK5 GK001 17q24.2 GK001 protein DDX42 17q24.2 DEAD (Asp-Glu-Ala-Asp) box polypeptide 42 FTSJ3 17q23 FtsJ homolog 3 (E. coli) PSMC5 17q24-q25 proteasome (prosome, macropain) 26S subunit, ATPase, 5 SMARCD2 17q23-q24 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 2 LOC388410 17 LOC388410 CSH2 17q23.3-q24.2 chorionic somatomammotropin hormone 2 GH2 17q23 growth hormone 2 CSH1 17q23.3-q24.2 chorionic somatomammotropin hormone 1 (placental lactogen) CSHL1 17q23.3-q24.2 chorionic somatomammotropin hormone-like 1 GH1 17q24 growth hormone 1 CD79B 17q23 CD79B antigen (immunoglobulin-associated beta) SCN4A 17q23 sodium channel, voltage-gated, type IV, alpha ICAM2 17q23-q25 intercellular adhesion molecule 2 ERN1 16p12 ER to nucleus signalling 1 FLJ30999 17q24.2 hypothetical protein FLJ30999 HT008 17q24.2 uncharacterized hypothalamus protein HT008 LOC253013 17q24.2 similar to ribosomal protein L31 PECAM1 17q23 platelet/endothelial cell adhesion molecule (CD31 antigen)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    22 - 4005 109.6 977 - 2009 19135427
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • kinase/RNase domains extended by 43AAs at its N terminus, a kinase domain activated by trans-autophosphorylation
  • a RNase domain in the cytosolic region
  • a luminal domain and cytosolic domain of ERN1 are thought to play crucial roles in regulating the protein activity
  • transmembrane domain playing a role in regulating the ERN1 protein activity
  • secondary structure
  • transmembrane domain of the ERN1 is alpha-helical in a membrane-like environment
  • HOMOLOGY
    interspecies homolog to murine Ern1 (93.3pc)
    homolog to rattus Ern1 (93.8pc)
    intraspecies
    Homologene
    FAMILY
  • protein kinase superfamily
  • Ser/Thr protein kinase family
  • CATEGORY enzyme , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,nucleus
    text
  • transported to the nucleus after proteolytic cleavage
  • ER-resident, type I transmembrane protein with a luminal domain sensing UPR and a cytosolic domain passing the signal on to components further downstream via its kinase and endoribonuclease (RNase) activities
  • basic FUNCTION
  • involved in electron transport, protein amino acid phosphorylation
  • has an intrinsic kinase activity and an endoribonuclease activity
  • has a unique function of relieving ER stress in cells
  • induces unconventional splicing of mRNA coding a specific transcription factor for activating the unfolded protein response
  • activating chaperone genes in response to stress in the ER and also activating JNK
  • promote cell survival by reducing misfolded protein levels
  • type I transmembrane Ser/Thr kinase that also has site-specific endoribonuclease (RNase) activity
  • induction of ER quality control proteins is mediated by ERN1 which activates the transcription factor XBP1 via an unconventional splicing event
  • oligomerizes in the ER membrane and oligomerization correlates with the onset of ERN1 phosphorylation and RNase activity
  • its activity is governed by a timer that may be important in switching the UPR (unfolded protein response) from the initially cytoprotective phase to the apoptotic mode
  • splices the precursor unspliced form of X-box–binding protein 1 messenger RNA (XBP1u mRNA) on the ER membrane to yield an active transcription factor (XBP1s), leading to the alleviation of the stress
  • endoribonuclease activity of ERN1 appears to be required for AMPK activation in response to nitric oxide
  • RNase activity of ERN11 participates in AMPK activation and subsequent signaling through multiple AMPK-dependent pathways in response to nitrosative stress
  • plays an essential role in ER stress-mediated aggregation of mutant HTT via the inhibition of autophagy flux and thus neuronal toxicity of mutant HTT aggregates in Huntington disease
  • ER stress sensor protein, activated via trans-autophosphorylation in response to ER stress triggered by thapsigargin or tunicamycin
  • directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding
  • couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the XBP1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs
  • role for ERN1 in building ER capacity but not in preserving ER integrity of stressed cells
  • ER transmembrane sensor that activates the unfolded protein response (UPR) to maintain the ER and cellular function
  • serine-threonine kinase that plays crucial roles in activating the unfolded protein response
  • regulatory function for ERN1 in the promotion of IL4 in T cells
  • has an inhibitory effect on respiratory syncytial virus (RSV) replication
  • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, transcription, regulation
    protein
    PHYSIOLOGICAL PROCESS electron transport
    PATHWAY
    metabolism
    signaling
    ERN1-XBP1 pathway is involved in osteoblast differentiation through promoting SP7 transcription
    a component
  • the cytosolic domain of IRE1alpha forms a complex with BAK1 and with BAX, complex that is essential for IRE1alpha activation
  • homodimer, disulfide-linked; dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges
  • INTERACTION
    DNA
    RNA
    small molecule metal binding, nucleotide,
  • ions Mg2+
  • ATP
  • protein
  • TRAF2 was proposed to bind to ERN1 during ER stress response
  • binds HSPA5, a negative regulator of the unfolded protein response (interaction may disrupt homodimerization and prevent activation of ERN1)
  • CD59 (complement defense 59) mRNA is a novel cleavage target of ERN1
  • directly binds to USP14 and the interaction between ERN1 and USP14 is inhibited by ER stress
  • HSPA1A binding to ERN1 enhances ERN1/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis
  • ERN1 target XBP1, and are essential for bone morphogenic protein 2-induced osteoblast differentiation
  • directs proteasomal and lysosomal degradation of misfolded rhodopsin
  • spliced XBP1 serves as an important effector of ERN1, activating its target genes
  • in contrast to its mode of binding ATF6 and unfolded proteins, HSPA5 binds to ERN1 and EIF2AK3 in a different manner
  • ERN1, ATF6, and EIF2AK3 signaling pathways, collectively called the unfolded protein response (UPR), regulate the functions of endoplasmic reticulum, responsible for accurate folding of membrane proteins such as RHO
  • cell & other
    REGULATION
    activated by BAX and BAK1
    endoplasmic reticulum stress, caused by the presence of misfolded proteins, that activates ERN1
    Other unfolded protein response (UPR) induction leads to proteolytic cleavage of ERN1
    phosphorylation is important in modulating ERN1 RNase activity which is achieved by increasing the propensity of ERN1 to dimerize
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorialvisualretina
    activation of ERN1 or ATF6 can selectively remove aggregated or mutant RHO from the cells and may be useful in treating RP associated with rhodopsin protein misfolding
    ANIMAL & CELL MODELS
  • in mice, IRE1alpha inactivation results in widespread developmental defects, leading to embryonic death after 12.5 days of gestation, and IRE1alpha was activated predominantly in the placenta
  • mammalian embryos lacking IRE1 (or its XBP1 effector) succumb early in embryonic development