Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm.
Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm.
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DOI：
10.1084/jem.20141157
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发表时间：
2015-04-06
期刊：
影响因子：
--
通讯作者：
Di Noia JM
中科院分区：
文献类型：
--
作者：
Methot SP;Litzler LC;Trajtenberg F;Zahn A;Robert F;Pelletier J;Buschiazzo A;Magor BG;Di Noia JM
Methot等人确定了细胞中活化诱导的脱氨酶（AID）的细胞质保留机制。AID与Hsp90和eEF1A蛋白的相互作用（两者都稳定AID）促进功能性AID在细胞质中的连续折叠和保留。抑制翻译延伸因子eEF 1A会阻止其与AID的相互作用，然后AID在细胞核中积累，增加类别转换重组和染色体易位副产物的产生。活化诱导的脱氨酶（AID）在免疫应答期间启动诱变途径以使抗体基因多样化。AID进入细胞核受到CRM1介导的细胞核输出和胞质滞留的未表征机制的限制。在这里，我们定义了AID中的构象基序，该基序决定了其胞质保留，并证明翻译延伸因子真核细胞延伸因子1 α（eEF1A）是AID胞质螯合所必需的。该机制独立于蛋白质合成，但依赖于eEF1A的无tRNA形式。抑制eEF1A可防止与AID的相互作用，AID在细胞核中积累并增加类别转换重组以及染色体易位副产物。大多数AID与未指明的胞浆复合体有关。我们发现AID与eEF 1A和热休克蛋白90 kD（HSP 90）的相互作用呈负相关。尽管这两种相互作用稳定了AID，但与HSP 90或eEF 1A相关的AID组分的性质是不同的，定义了两种复合物，它们依次在细胞质中产生和储存功能性AID。此外，核输出和胞质保留合作，排除从核AID，但可能不是功能等同的。我们的研究结果阐明了艾滋病胞质滞留的分子基础，定义其功能相关性，并将其与其他调节艾滋病的机制区分开来。
Methot et al. identify a mechanism for cytoplasmic retention of activation-induced deaminase (AID) in cells. Interactions of AID with Hsp90 and eEF1A proteins, both of which stabilize AID, promote sequential folding and retention of functional AID in the cytoplasm. Inhibition of the translation elongation factor eEF1A blocks its interaction with AID, which then accumulates in the nucleus, increasing class switch recombination and the generation of chromosomal translocation byproducts. Activation-induced deaminase (AID) initiates mutagenic pathways to diversify the antibody genes during immune responses. The access of AID to the nucleus is limited by CRM1-mediated nuclear export and by an uncharacterized mechanism of cytoplasmic retention. Here, we define a conformational motif in AID that dictates its cytoplasmic retention and demonstrate that the translation elongation factor eukaryotic elongation factor 1 α (eEF1A) is necessary for AID cytoplasmic sequestering. The mechanism is independent of protein synthesis but dependent on a tRNA-free form of eEF1A. Inhibiting eEF1A prevents the interaction with AID, which accumulates in the nucleus and increases class switch recombination as well as chromosomal translocation byproducts. Most AID is associated to unspecified cytoplasmic complexes. We find that the interactions of AID with eEF1A and heat-shock protein 90 kD (HSP90) are inversely correlated. Despite both interactions stabilizing AID, the nature of the AID fractions associated with HSP90 or eEF1A are different, defining two complexes that sequentially produce and store functional AID in the cytoplasm. In addition, nuclear export and cytoplasmic retention cooperate to exclude AID from the nucleus but might not be functionally equivalent. Our results elucidate the molecular basis of AID cytoplasmic retention, define its functional relevance and distinguish it from other mechanisms regulating AID.
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影响因子：
7.3
作者：
Marco, E;Martín-Santamaría, S;Gago, F
通讯作者：
Gago, F
DOI：
10.1084/jem.20040373
发表时间：
2004-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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Nussenzweig MC
影响因子：
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作者：
Brar, SS;Watson, M;Diaz, M
通讯作者：
Diaz, M
DOI：
10.1073/pnas.0810808106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Geisberger, Roland;Rada, Cristina;Neuberger, Michael S.
通讯作者：
Neuberger, Michael S.
DOI：
10.1073/pnas.1106729108
发表时间：
2011-11-08
影响因子：
11.1
作者：
Haesler, Julien;Rada, Cristina;Neuberger, Michael S.
通讯作者：
Neuberger, Michael S.