DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice

Tomomi Sakai, Takuya Miyazaki, Dong Mi Shin, Yong Soo Kim, Chen Feng Qi, Robert Fariss, Jeeva Munasinghe, Hongsheng Wang, Alexander L. Kovalchuk, Parul H. Kothari, Charles S. Fermaintt, John P. Atkinson, Fred W. Perrino, Nan Yan, Herbert C. Morse

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

TREX1/DNASE III, the most abundant 3'-5' DNA exonuclease in mammalian cells, is tail-anchored on the endoplasmic reticulum (ER). Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosacchryltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE). Here we investigate mice with conditional expression of the most common RVCL mutation, V235fs, and another mouse expressing a conditional C-terminal mutation, D272fs, associated with a case of human SLE. Mice homozygous for either mutant allele express the encoded human TREX1 truncations without endogenous mouse TREX1, and both remain DNase active in tissues. The two mouse strains are similar phenotypically without major signs of retinal, cerebral or renal disease but exhibit striking elevations of autoantibodies in the serum. The broad range of autoantibodies is primarily against non-nuclear antigens, in sharp contrast to the predominantly DNA-related autoantibodies produced by a TREX1-D18N mouse that specifically lacks DNase activity. We also found that treatment with an OST inhibitor, aclacinomycin, rapidly suppressed autoantibody production in the TREX1 frame-shift mutant mice. Together, our study presents two new mouse models based on TREX1 frame-shift mutations with a unique set of serologic autoimmune-like phenotypes.

Original languageEnglish (US)
JournalJournal of Autoimmunity
DOIs
StateAccepted/In press - Jan 11 2017

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Deoxyribonucleases
Autoimmunity
Autoantibodies
Mutation
Endoplasmic Reticulum
Systemic Lupus Erythematosus
Exodeoxyribonucleases
Aicardi Syndrome
Phosphodiesterase I
Frameshift Mutation
Tail
Alleles
Phenotype
Kidney
Antigens
DNA
Serum

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sakai, T., Miyazaki, T., Shin, D. M., Kim, Y. S., Qi, C. F., Fariss, R., ... Morse, H. C. (Accepted/In press). DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2017.03.001

DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. / Sakai, Tomomi; Miyazaki, Takuya; Shin, Dong Mi; Kim, Yong Soo; Qi, Chen Feng; Fariss, Robert; Munasinghe, Jeeva; Wang, Hongsheng; Kovalchuk, Alexander L.; Kothari, Parul H.; Fermaintt, Charles S.; Atkinson, John P.; Perrino, Fred W.; Yan, Nan; Morse, Herbert C.

In: Journal of Autoimmunity, 11.01.2017.

Research output: Contribution to journalArticle

Sakai, T, Miyazaki, T, Shin, DM, Kim, YS, Qi, CF, Fariss, R, Munasinghe, J, Wang, H, Kovalchuk, AL, Kothari, PH, Fermaintt, CS, Atkinson, JP, Perrino, FW, Yan, N & Morse, HC 2017, 'DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice', Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2017.03.001
Sakai, Tomomi ; Miyazaki, Takuya ; Shin, Dong Mi ; Kim, Yong Soo ; Qi, Chen Feng ; Fariss, Robert ; Munasinghe, Jeeva ; Wang, Hongsheng ; Kovalchuk, Alexander L. ; Kothari, Parul H. ; Fermaintt, Charles S. ; Atkinson, John P. ; Perrino, Fred W. ; Yan, Nan ; Morse, Herbert C. / DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. In: Journal of Autoimmunity. 2017.
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abstract = "TREX1/DNASE III, the most abundant 3'-5' DNA exonuclease in mammalian cells, is tail-anchored on the endoplasmic reticulum (ER). Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Gouti{\`e}res syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosacchryltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE). Here we investigate mice with conditional expression of the most common RVCL mutation, V235fs, and another mouse expressing a conditional C-terminal mutation, D272fs, associated with a case of human SLE. Mice homozygous for either mutant allele express the encoded human TREX1 truncations without endogenous mouse TREX1, and both remain DNase active in tissues. The two mouse strains are similar phenotypically without major signs of retinal, cerebral or renal disease but exhibit striking elevations of autoantibodies in the serum. The broad range of autoantibodies is primarily against non-nuclear antigens, in sharp contrast to the predominantly DNA-related autoantibodies produced by a TREX1-D18N mouse that specifically lacks DNase activity. We also found that treatment with an OST inhibitor, aclacinomycin, rapidly suppressed autoantibody production in the TREX1 frame-shift mutant mice. Together, our study presents two new mouse models based on TREX1 frame-shift mutations with a unique set of serologic autoimmune-like phenotypes.",
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AU - Sakai, Tomomi

AU - Miyazaki, Takuya

AU - Shin, Dong Mi

AU - Kim, Yong Soo

AU - Qi, Chen Feng

AU - Fariss, Robert

AU - Munasinghe, Jeeva

AU - Wang, Hongsheng

AU - Kovalchuk, Alexander L.

AU - Kothari, Parul H.

AU - Fermaintt, Charles S.

AU - Atkinson, John P.

AU - Perrino, Fred W.

AU - Yan, Nan

AU - Morse, Herbert C.

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