DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice.
DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice.
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DOI：
10.1016/j.jaut.2017.03.001
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发表时间：
2017-07
影响因子：
12.8
通讯作者：
Morse HC 3rd
中科院分区：
文献类型：
--
作者：
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 3rd
TREX 1/DNASE III是哺乳动物细胞中最丰富的3′-5′ DNA外切核酸酶，尾锚定在内质网（ER）上。影响TREX 1 DNA酶活性的N-末端突变与自身免疫性和炎症性疾病相关，如Aicardi-Goutières综合征（AGS）。TREX 1的C末端突变导致ER定位缺失和寡糖基转移酶（OST）活性失调，并与视网膜血管病变伴脑白质营养不良（RVCL）相关，在某些情况下与系统性红斑狼疮（SLE）相关。在这里，我们调查小鼠与条件表达最常见的RVCL突变，V235 fs，和另一种小鼠表达条件C-末端突变，D272 fs，与人类SLE的情况下。对于任一突变等位基因纯合的小鼠表达编码的人TREX 1截短，而没有内源性小鼠TREX 1，并且两者在组织中保持DNA酶活性。两种小鼠品系在表型上相似，没有视网膜、脑或肾脏疾病的主要体征，但血清中自身抗体显著升高。广泛的自身抗体主要针对非核抗原，与由特异性缺乏DNA酶活性的TREX 1-D18 N小鼠产生的主要与DNA相关的自身抗体形成鲜明对比。我们还发现，用OST抑制剂阿克拉霉素治疗，迅速抑制TREX 1移码突变小鼠中自身抗体的产生。总之，我们的研究提出了两个新的小鼠模型的基础上TREX 1移码突变与一组独特的血清学自身免疫样表型。
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.
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影响因子：
64.5
作者：
Stetson DB;Ko JS;Heidmann T;Medzhitov R
通讯作者：
Medzhitov R
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
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DOI：
10.1084/jem.20061041
发表时间：
2006-10-30
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Fagarasan S
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影响因子：
30.5
作者：
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影响因子：
11.2
作者：
Shin DM;Shaffer DJ;Wang H;Roopenian DC;Morse HC 3rd
通讯作者：
Morse HC 3rd