The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ''ERN1'' gene.

Function

The protein encoded by this gene 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). 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) mRNA, and allowing it to become translated into a functional transcription factor, XBP1s. XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation ( ERAD) genes that facilitate recovery from ER stress.

Clinical significance

As IRE1α is a primary sensor for unfolded protein response, 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 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 with Heat shock protein 90kDa alpha (cytosolic), member A1.

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.