The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that in humans is encoded by the ''ERN1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

The protein encoded by this

is the ER to nucleus signalling 1 protein, a human homologue of the yeast Ire1 gene product. This protein possesses intrinsic

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the

unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Signaling

IRE1α possesses two functional enzymatic domains, an

endonuclease Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases ...

and a trans-autophosphorylation kinase domain. Upon activation, IRE1α oligomerizes and carries out an unconventional RNA splicing activity, removing an

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

from the X-box binding protein 1 (

XBP1 X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the ''XBP1'' gene. The ''XBP1'' gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP ...

) mRNA, and allowing it to become translated into a functional

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

, XBP1s. XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (

ERAD Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the prote ...

) genes that facilitate recovery from ER stress.

Clinical significance

As IRE1α is a primary sensor for

, its disruption could be linked with

neurodegenerative diseases A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

, by which the accumulation of intracellular toxic proteins serves as one of the key pathogenic mechanisms. IRE1 signalling is considered to be pathogenic in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

and

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

Research

''ERN1'' is overexpressed in the direct iPSC-derived motor neurons generated from familial ALS patients’ blood, and suppressing ''Ire1'' in the C9orf72-ALS fly model impeded eye degeneration.

Interactions

ERN1 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

Heat shock protein 90kDa alpha (cytosolic), member A1 Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the ''HSP90AA1'' gene. Function The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expr ...

Inhibitors

Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain.

RNase domain inhibitors

Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde, 4μ8C, MKC-3946, STF-083010, toyocamycin.

ATP-binding pocket

Sunitinib Sunitinib, sold under the brand name Sutent, is a medication used to treat cancer. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and i ...

and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain. Compound 3 prevents kinase activity, oligomerization and RNase activity.