InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: TREX1

Summary

InnateDB Protein

IDBP-376021.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

TREX1

Protein Name

three prime repair exonuclease 1

Synonyms

AGS1; CRV; DRN3; HERNS;

Species

Homo sapiens

Ensembl Protein

ENSP00000392569

InnateDB Gene

IDBG-239077 (TREX1)

Protein Structure

UniProt Annotation

Function

Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini. Prevents cell-intrinsic initiation of autoimmunity. Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements. Unless degraded, these DNA fragments accumulate in the cytosol and activate the IFN-stimulatory DNA (ISD) response and innate immune signaling. Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates. Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light. During GZMA-mediated cell death, contributes to DNA damage in concert with NME1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair. {ECO:0000269PubMed:10391904, ECO:0000269PubMed:10393201, ECO:0000269PubMed:16818237, ECO:0000269PubMed:17293595, ECO:0000269PubMed:18045533, ECO:0000269PubMed:23993650}.

Subcellular Localization

Nucleus. Cytoplasm, cytosol. Endoplasmic reticulum membrane; Peripheral membrane protein. Note=Retained in the cytoplasm through the C-terminal region (By similarity). In response to DNA damage, translocates to the nucleus where it is specifically recruited to replication foci. Translocation to the nucleus also occurs during GZMA-mediated cell death. {ECO:0000250}.

Disease Associations

Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269PubMed:16845398, ECO:0000269PubMed:17357087, ECO:0000269PubMed:17846997, ECO:0000269PubMed:20131292, ECO:0000269PubMed:20799324}. Note=The disease is caused by mutations affecting the gene represented in this entry.Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269PubMed:17660818, ECO:0000269PubMed:20131292}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV- light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto- immune reactivity and eventually skin lesions (PubMed:23993650). {ECO:0000269PubMed:23993650}.Chilblain lupus 1 (CHBL1) [MIM:610448]: A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. {ECO:0000269PubMed:17357087, ECO:0000269PubMed:17440703}. Note=The disease is caused by mutations affecting the gene represented in this entry.Vasculopathy, retinal, with cerebral leukodystrophy (RVCL) [MIM:192315]: A microvascular endotheliopathy resulting in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. {ECO:0000269PubMed:17660820}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Detected in thymus, spleen, liver, brain, heart, small intestine and colon. {ECO:0000269PubMed:10393201, ECO:0000269PubMed:11278605}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 7 experimentally validated interaction(s) in this database.

Experimentally validated
Total	7 [view]
Protein-Protein	7 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003676	nucleic acid binding
GO:0003697	single-stranded DNA binding
GO:0004527	exonuclease activity
GO:0008296	3'-5'-exodeoxyribonuclease activity
GO:0008408	3'-5' exonuclease activity
GO:0008853	exodeoxyribonuclease III activity
GO:0032405	MutLalpha complex binding
GO:0032407	MutSalpha complex binding
GO:0042803	protein homodimerization activity
GO:0046872	metal ion binding

Biological Process

GO:0000738	DNA catabolic process, exonucleolytic
GO:0006259	DNA metabolic process
GO:0006260	DNA replication
GO:0006281	DNA repair
GO:0006298	mismatch repair
GO:0006310	DNA recombination
GO:0008219	cell death
GO:0032479	regulation of type I interferon production
GO:0032481	positive regulation of type I interferon production
GO:0045087	innate immune response
GO:0090305	nucleic acid phosphodiester bond hydrolysis