A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus.
A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus.
复制标题
由复杂小鼠逆转录病毒编码的激活诱导胞苷脱氨酶的蛋白质拮抗剂。
DOI：
10.1128/mbio.01678-19
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发表时间：
2019
期刊：
影响因子：
6.4
通讯作者：
Dudley,JaquelinP
中科院分区：
文献类型：
--
作者：
Singh,GurvaniB;Byun,Hyewon;Ali,AlmasF;Medina,Frank;Wylie,Dennis;Shivram,Haridha;Nash,AndreaK;Lozano,MaryM;Dudley,JaquelinP
复杂的人类致病性逆转录病毒在世界范围内引起高发病率和死亡率，但由于逃避免疫反应而抵抗抗病毒药物和疫苗的开发。小鼠乳腺肿瘤病毒（MMTV）是一种复杂的逆转录病毒，需要在B淋巴细胞和T淋巴细胞中复制才能在乳腺传播，并被先天免疫限制因子小鼠Apobec3 （mA3）拮抗。为了确定调节/辅助蛋白Rem是否影响对MMTV的先天反应，将缺乏Rem表达的剪接供体突变体（MMTV- sd）注射到BALB/c小鼠中。MMTV- sd诱导的乳腺肿瘤比野生型MMTV （MMTV- wt）诱导的乳腺肿瘤具有更低的前病毒载量、更低的发病率和更长的潜伏期。MMTV-SD原病毒在原病毒正链上有许多G-to-A突变，但在WRC基序内也有C-to-T转变。同样，与野生型病毒诱导的肿瘤相比，缺乏Rem表达的淋巴瘤源性MMTV变体显示出前病毒载量减少和WRC基序突变增加，这与淋巴样细胞中激活诱导的胞苷脱氨酶（AID）突变一致。这些突变是Apobec家族成员AID的典型突变，AID是一种参与抗体可变区超突变的b细胞特异性诱变蛋白。相比之下，来自aids不足小鼠肿瘤的MMTV-WT和MMTV-SD前病毒的WRC基序突变和原病毒载量相似。AID没有包装在MMTV病毒粒子中。转染实验中Rem共表达导致AID蛋白酶体降解。我们的数据表明，remi指定了一种人类免疫缺陷病毒1型（HIV-1） vif样蛋白，该蛋白在淋巴细胞中MMTV复制过程中抑制AID并拮抗先天免疫。复杂的逆转录病毒，如人类免疫缺陷病毒1型（HIV-1），导致许多人死亡。这些逆转录病毒通过干扰宿主免疫的病毒蛋白产生终身感染。复杂逆转录病毒小鼠乳腺肿瘤病毒（MMTV）允许研究宿主-病原体相互作用，这在人类中是不可能的。在两种不同的MMTV菌株中，阻止MMTV Rem蛋白表达的突变降低了肿瘤中的前病毒载量，并增加了一种进化上古老的酶AID的典型病毒基因组突变。虽然艾滋病的存在通常会改善基于抗体的免疫，但它可能有助于人类癌症的进展。我们观察到MMTV Rem和AID的共表达导致AID的破坏。我们的研究结果表明，Rem是第一个已知的AID蛋白抑制剂，进一步的实验可能会带来新的疾病治疗方法。
Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest thatremspecifies a human immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.IMPORTANCEComplex retroviruses, such as human immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.