Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Review Article

TREX1 As a Potential Therapeutic Target for Autoimmune and Inflammatory Diseases

Author(s): Sha-Sha Tao*, Guo-Cui Wu, Qin Zhang, Tian-Ping Zhang, Rui-Xue Leng, Hai-Feng Pan and Dong-Qing Ye

Volume 25 , Issue 30 , 2019

Page: [3239 - 3247] Pages: 9

DOI: 10.2174/1381612825666190902113218

Price: $65


Background and Objectives: The 3’ repair exonuclease 1 (TREX1) gene is the major DNA-specific 3’–5 ’exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that protects the host from inappropriate autoimmune activations. It has been revealed that TREX1 function is necessary to prevent host DNA accumulating after cell death which could actuate an autoimmune response. In the manuscript, we will discuss in detail the latest advancement to study the role of TREX1 in autoimmune disease.

Methods: As a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as an antiinflammatory molecule, the functional mechanisms of TREX1 were multifactorial. In this review, we will briefly summarize the latest advancement in studying the role of TREX1 in autoimmune disease, and discuss its potential as a therapeutic target for these diseases.

Results: Deficiency of TREX1 in human patients and murine models is characterized by systemic inflammation and the disorder of TREX1 functions drives inflammatory responses leading to autoimmune disease. Moreover, much more studies revealed that mutations in TREX1 have been associated with a range of autoimmune disorders. But it is also unclear whether the mutations of TREX1 play a causal role in the disease progression, and whether manipulation of TREX1 has a beneficial effect in the treatment of autoimmune diseases.

Conclusion: Integration of functional TREX1 biology into autoimmune diseases may further deepen our understanding of the development and pathogenesis of autoimmune diseases and provide new clues and evidence for the treatment of autoimmune diseases.

Keywords: TREX, autoimmune diseases, autoimmunity, single- and double-stranded DNA, nucleic acid, cell death.

Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 2007; 131(5): 873-86.
[] [PMID: 18045533]
Barizzone N, Monti S, Mellone S, et al. Rare variants in the TREX1 gene and susceptibility to autoimmune diseases. BioMed Res Int 2013; 2013471703
[] [PMID: 24224166]
Miyazaki T, Kim YS, Yoon J, Wang H, Suzuki T, Morse HC III. The 3′-5′ DNA exonuclease TREX1 directly interacts with poly(ADP-ribose) polymerase-1 (PARP1) during the DNA damage response. J Biol Chem 2014; 289(47): 32548-58.
[] [PMID: 25278026]
Abe J, Nakamura K, Nishikomori R, et al. A nationwide survey of Aicardi-Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study. Rheumatology (Oxford) 2014; 53(3): 448-58.
[] [PMID: 24300241]
Olivieri I, Cattalini M, Tonduti D, et al. Dysregulation of the immune system in Aicardi-Goutières syndrome: Another example in a TREX1-mutated patient. Lupus 2013; 22(10): 1064-9.
[] [PMID: 23918923]
Günther C, Meurer M, Stein A, Viehweg A, Lee-Kirsch MA. Familial chilblain lupus-a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1. Dermatology (Basel) 2009; 219(2): 162-6.
[] [PMID: 19478477]
Günther C, Berndt N, Wolf C, Lee-Kirsch MA. Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3′ repair exonuclease 1 (TREX1). JAMA Dermatol 2015; 151(4): 426-31.
[] [PMID: 25517357]
DiFrancesco JC, Novara F, Zuffardi O, et al. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol Sci 2015; 36(2): 323-30.
[] [PMID: 25213617]
Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007; 39(9): 1068-70.
[] [PMID: 17660820]
Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 2007; 39(9): 1065-7.
[] [PMID: 17660818]
Ellyard JI, Jerjen R, Martin JL, et al. Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing. Arthritis Rheumatol 2014; 66(12): 3382-6.
[] [PMID: 25138095]
Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 2014; 192(12): 5993-7.
[] [PMID: 24813208]
Morita M, Stamp G, Robins P, et al. Gene-targeted mice lacking the Trex1 (DNase III) 3′-->5′ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol 2004; 24(15): 6719-27.
[] [PMID: 15254239]
Lehtinen DA, Harvey S, Mulcahy MJ, Hollis T, Perrino FW. The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease. J Biol Chem 2008; 283(46): 31649-56.
[] [PMID: 18805785]
Chowdhury D, Beresford PJ, Zhu P, et al. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell 2006; 23(1): 133-42.
[] [PMID: 16818237]
Kucej M, Fermaintt CS, Yang K, Irizarry-Caro RA, Yan N. Mitotic phosphorylation of TREX1 C terminus disrupts TREX1 regulation of the Oligosaccharyltransferase complex. Cell Rep 2017; 18(11): 2600-7.
[] [PMID: 28297665]
Bailey SL, Harvey S, Perrino FW, Hollis T. Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease. DNA Repair (Amst) 2012; 11(1): 65-73.
[] [PMID: 22071149]
Huang KW, Liu TC, Liang RY, et al. Structural basis for overhang excision and terminal unwinding of DNA duplexes by TREX1. PLoS Biol 2018; 16(5) e2005653
Wolf C, Rapp A, Berndt N, et al. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun 2016; 7: 11752.
[] [PMID: 27230542]
Yan N. Immune diseases associated with TREX1 and STING dysfunction. J Interferon Cytokine Res 2017; 37(5): 198-206.
[] [PMID: 28475463]
Pereira-Lopes S, Celhar T, Sans-Fons G, et al. The exonuclease Trex1 restrains macrophage proinflammatory activation. J Immunol 2013; 191(12): 6128-35.
[] [PMID: 24218451]
Gall A, Treuting P, Elkon KB, et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 2012; 36(1): 120-31.
[] [PMID: 22284419]
Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 2008; 134(4): 587-98.
[] [PMID: 18724932]
Rego SL, Harvey S, Simpson SR, et al. TREX1 D18N mice fail to process erythroblast DNA resulting in inflammation and dysfunctional erythropoiesis. Autoimmunity 2018; 1-12.
[] [PMID: 30422000]
de Silva U, Choudhury S, Bailey SL, Harvey S, Perrino FW, Hollis T. The crystal structure of TREX1 explains the 3′ nucleotide specificity and reveals a polyproline II helix for protein partnering. J Biol Chem 2007; 282(14): 10537-43.
[] [PMID: 17293595]
Kavanagh D, Spitzer D, Kothari PH, et al. New roles for the major human 3′-5′ exonuclease TREX1 in human disease. Cell Cycle 2008; 7(12): 1718-25.
[] [PMID: 18583934]
Ablasser A, Hertrich C, Waßermann R, Hornung V. Nucleic acid driven sterile inflammation. Clin Immunol 2013; 147(3): 207-15.
[] [PMID: 23419883]
Orebaugh CD, Fye JM, Harvey S, Hollis T, Wilkinson JC, Perrino FW. The TREX1 C-terminal region controls cellular localization through ubiquitination. J Biol Chem 2013; 288(40): 28881-92.
[] [PMID: 23979357]
Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15(1): 49-54.
[] [PMID: 6712192]
Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet 2007; 81(4): 713-25.
[] [PMID: 17846997]
Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 2006; 38(8): 917-20.
[] [PMID: 16845398]
Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet 2007; 80(4): 811-5.
[] [PMID: 17357087]
Haaxma CA, Crow YJ, van Steensel MA, et al. A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutières syndrome. Am J Med Genet A 2010; 152A(10): 2612-7.
[] [PMID: 20799324]
Crow YJ, Livingston JH. Aicardi-Goutières syndrome: An important Mendelian mimic of congenital infection. Dev Med Child Neurol 2008; 50(6): 410-6.
[] [PMID: 18422679]
Lindahl T, Barnes DE, Yang YG, Robins P. Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease. Biochem Soc Trans 2009; 37(Pt 3): 535-8.
[] [PMID: 19442247]
Tüngler V, Silver RM, Walkenhorst H, Günther C, Lee-Kirsch MA. Inherited or de novo mutation affecting aspartate 18 of TREX1 results in either familial chilblain lupus or Aicardi-Goutières syndrome. Br J Dermatol 2012; 167(1): 212-4.
[] [PMID: 22356656]
Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum 2010; 62(5): 1469-77.
[] [PMID: 20131292]
Abe J, Izawa K, Nishikomori R, et al. Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. Rheumatology (Oxford) 2013; 52(2): 406-8.
[] [PMID: 22829693]
Kamei A, Akasaka M, Soga N, Suzuki Y, Uchide M, Chida S. Aicardi-Goutières syndrome with systemic lupus erythematosus and hypothyroidism. Brain Dev 2013; 35(1): 87-90.
[] [PMID: 22521435]
De Laet C, Goyens P, Christophe C, Ferster A, Mascart F, Dan B. Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutières syndrome. Neuropediatrics 2005; 36(6): 399-402.
[] [PMID: 16429382]
Xiao N, Wei J, Xu S, et al. cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model. J Autoimmun 2019; 100: 84-94.
[] [PMID: 30872080]
Nick McElhinny SA, Kumar D, Clark AB, et al. Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 2010; 6(10): 774-81.
[] [PMID: 20729855]
Shaban NM, Harvey S, Perrino FW, Hollis T. The structure of the mammalian RNase H2 complex provides insight into RNA.NA hybrid processing to prevent immune dysfunction. J Biol Chem 2010; 285(6): 3617-24.
[] [PMID: 19923215]
Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med 2012; 209(8): 1419-26.
[] [PMID: 22802351]
Reijns MA, Rabe B, Rigby RE, et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 2012; 149(5): 1008-22.
[] [PMID: 22579044]
Goldstone DC, Ennis-Adeniran V, Hedden JJ, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 2011; 480(7377): 379-82.
[] [PMID: 22056990]
Powell RD, Holland PJ, Hollis T, Perrino FW. Aicardi-Goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase. J Biol Chem 2011; 286(51): 43596-600.
[] [PMID: 22069334]
Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 2010; 11(11): 1005-13.
[] [PMID: 20871604]
Lee-Kirsch MA, Gong M, Schulz H, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 2006; 79(4): 731-7.
[] [PMID: 16960810]
Lee-Kirsch MA. The type I interferonopathies. Annu Rev Med 2017; 68: 297-315.
[] [PMID: 27813875]
Sugiura K, Takeichi T, Kono M, et al. Severe chilblain lupus is associated with heterozygous missense mutations of catalytic amino acids or their adjacent mutations in the exonuclease domains of 3′-repair exonuclease 1. J Invest Dermatol 2012; 132(12): 2855-7.
[] [PMID: 22718116]
Yamashiro K, Tanaka R, Li Y, Mikasa M, Hattori NA. TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus. J Neurol 2013; 260(10): 2653-5.
[] [PMID: 23989343]
Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A 2011; 155A(1): 235-7.
[] [PMID: 21204240]
Federico A, Di Donato I, Bianchi S, Di Palma C, Taglia I, Dotti MT. Hereditary cerebral small vessel diseases: a review. J Neurol Sci 2012; 322(1-2): 25-30.
[] [PMID: 22868088]
Soong BW, Liao YC, Tu PH, et al. A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain. J Chin Med Assoc 2013; 76(6): 319-24.
[] [PMID: 23602593]
Yamamoto Y, Craggs L, Baumann M, Kalimo H, Kalaria RN. Review: molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathol Appl Neurobiol 2011; 37(1): 94-113.
[] [PMID: 21062344]
de Boer I, van den Maagdenberg AMJM, Terwindt GM. TREX1 Mutation causing autosomal dominant thrombotic microangiopathy and CKD is in fact a case of RVCL-S presenting with renal features. Am J Kidney Dis 2019; 73(6): 893.
[] [PMID: 30846258]
Vodopivec I, Oakley DH, Perugino CA, Venna N, Hedley-Whyte ET, Stone JHAA. 44-year-old man with eye, kidney, and brain dysfunction. Ann Neurol 2016; 79(4): 507-19.
[] [PMID: 26691497]
Stam AH, Kothari PH, Shaikh A, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain 2016; 139(11): 2909-22.
[] [PMID: 27604306]
Gulati A, Dahl N. In reply to ‘TREX1 mutation causing autosomal dominant thrombotic microangiopathy and CKD is in fact a case of RVCL-S presenting with renal features’. Am J Kidney Dis 2019; 73(6): 893-4.
[] [PMID: 30846257]
Hardy TA, Young S, Sy JS, et al. Tumefactive lesions in retinal vasculopathy with cerebral leucoencephalopathy and systemic manifestations (RVCL-S): a role for neuroinflammation? J Neurol Neurosurg Psychiatry 2017. pii: jnnp-2017-316142.
[PMID: 28794152]
Sakai T, Miyazaki T, Shin DM, et al. DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. J Autoimmun 2017; 81: 13-23.
[] [PMID: 28325644]
Monroy-Jaramillo N, Cerón A, León E, et al. Phenotypic variability in a mexican mestizo family with retinal vasculopathy with cerebral leukodystrophy and TREX1 mutation p.V235Gfs*6. Rev Invest Clin 2018; 70(2): 68-75.
[] [PMID: 29718010]
Saito R, Nozaki H, Kato T, et al. Retinal vasculopathy with cerebral leukodystrophy: Clinicopathologic features of an autopsied patient with a heterozygous TREX 1 mutation. J Neuropathol Exp Neurol 2019; 78(2): 181-6.
[] [PMID: 30561700]
Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358(9): 929-39.
[] [PMID: 18305268]
Lee HS, Bae SC. What can we learn from genetic studies of systemic lupus erythematosus? Implications of genetic heterogeneity among populations in SLE. Lupus 2010; 19(12): 1452-9.
[] [PMID: 20947557]
de Vries B, Steup-Beekman GM, Haan J, et al. TREX1 gene variant in neuropsychiatric systemic lupus erythematosus. Ann Rheum Dis 2010; 69(10): 1886-7.
[] [PMID: 19875384]
Namjou B, Kothari PH, Kelly JA, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 2011; 12(4): 270-9.
[] [PMID: 21270825]
Yamazaki T, Galluzzi L. TREX1 Cuts down on cancer immunogenicity. Trends Cell Biol 2017; 27(8): 543-5.
[] [PMID: 28625463]
An J, Woodward JJ, Lai W, et al. Inhibition of cyclic GMP-AMP synthase using a novel antimalarial drug derivative in Trex1-deficient mice. Arthritis Rheumatol 2018; 70(11): 1807-19.
[] [PMID: 29781188]
Briand C, Frémond ML, Bessis D, et al. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency. Ann Rheum Dis 2019; 78(3): 431-3.
[] [PMID: 30282666]
Zimmermann N, Wolf C, Schwenke R, et al. Assessment of clinical response to janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation. JAMA Dermatol 2019; 155(3): 342-6.
[] [PMID: 30673078]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy