Disruption of the association of 73 kDa heat shock cognate protein with transporters associated with antigen processing (TAP) decreases TAP-dependent translocation of antigenic peptides into the endoplasmic reticulum
Disruption of the association of 73 kDa heat shock cognate protein with transporters associated with antigen processing (TAP) decreases TAP-dependent translocation of antigenic peptides into the endoplasmic reticulum
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DOI：
10.1111/j.1348-0421.2008.00017.x
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发表时间：
2008-02-01
影响因子：
2.6
通讯作者：
Sato, Noriyuki
中科院分区：
文献类型：
--
作者：
Kamiguchi, Kenjiro;Torigoe, Toshihiko;Sato, Noriyuki
在胞质溶胶中产生的主要组织相容性复合物I类结合的抗原肽通过TAP易位到ER中。在本研究中，证明了HSC 73与人淋巴母细胞样T I细胞中的TAP的物理关联。在10 mM ATP存在下诱导解离，表明HSC 73的ADP结合形式可能与TAP相关。我们发现HSC 73结合免疫抑制剂MeDSG破坏了HSC 73-TAP的结合，而它不影响HSC 73与底物蛋白的结合。细胞表面的MHC I类分子表达也下调。然后，使用两种同源模型肽NGT-Bw 4和NGT-Bw 6来检查MeDSG对TAP介导的ER易位的影响，所述同源模型肽NGT-Bw 4和NGT-Bw 6对HSC 73具有不同的结合亲和力。尽管高亲和力肽NGT-Bw 4被TAP移位，但低亲和力肽NGT-Bw 6不被TAP移位。在MeDSG存在下，NGT-Bw 4的TAP依赖性易位被消除。在MeDSG存在下，对HSC 73具有高亲和力的人白细胞抗原（HLA）-A31限制性天然抗原肽F4.2显示出细胞表面上的呈递减少。结果表明，HSC 73-TAP缔合的破坏导致HSC 73结合肽的TAP依赖性易位的抑制。我们的研究结果突出了HSC 73的重要作用，为饲料抗原肽TAP，并提出了一种可能性，即合成的多胺可能会抑制HSC 73的功能，从而抑制MHC I类限制的介绍HSC 73结合的抗原肽。
Major histocompatibility complex class I-bound antigenic peptides generated in the cytosol are translocated into the ER by TAP. In the present study, the physical association of HSC73 with TAP in human lymphoblastoid T I cells was demonstrated. The dissociation was induced in the presence of 10mM ATP, indicating that the ADP-binding form of HSC73 might be associated with TAP. We found that HSC73-binding immunosuppressant, MeDSG disrupted the HSC73-TAP association, whereas it did not affect the binding of HSC73 to a substrate protein. MHC class I expression on the cell surface was also downregulated. Then, the effect of MeDSG on the TAP-mediated ER translocation was examined using two homologous model peptides, NGT-Bw4 and NGT-Bw6, which had distinct binding affinity to HSC73. Although high-affinity peptide NGT-Bw4 was translocated by TAP, low-affinity peptide NGT-Bw6 was not. The TAP-dependent translocation of NGT-Bw4 was abolished in the presence of MeDSG. Decreased presentation on the cell surface was shown for the human leukocyte antigen (HLA) -A31-restricted natural antigenic peptide F4.2, which had high affinity to HSC73, in the presence of MeDSG. It was indicated that disruption of the HSC73-TAP association resulted in inhibition of TAP-dependent translocation of HSC73-bound peptides. Our findings highlighted an important role of HSC73 for feeding antigenic peptides to TAP, and suggested a possibility that a synthetic polyamine might inhibit the function of HSC73, thereby suppressing MHC class I-restricted presentation of HSC73-bound antigenic peptides.