DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice.
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 oligosaccharyltransferase (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.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Tomomi
T
Sakai
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
Takuya
T
Miyazaki
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA; Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea.
Dong-Mi
DM
Shin
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
Yong-Soo
YS
Kim
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
Chen-Feng
CF
Qi
Biological Imaging Core Facility, National Eye Institute, NIH, Bethesda, MD, USA.
Robert
R
Fariss
In Vivo NMR Center, National Institute of Neurologic Diseases and Stroke, Bethesda, MD, USA.
Jeeva
J
Munasinghe
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
Hongsheng
H
Wang
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
Alexander L
AL
Kovalchuk
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
Parul H
PH
Kothari
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Charles S
CS
Fermaintt
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
John P
JP
Atkinson
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Fred W
FW
Perrino
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Nan.Yan@UTSouthwestern.edu.
Nan
N
Yan
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA. Electronic address: HMORSE@niaid.nih.gov.
Herbert C
HC
Morse
D015250:Aclarubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome
D001323:Autoantibodies; D010750:Phosphoproteins; C011157:aclacinomycins; D015250:Aclarubicin; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1