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鉴定对单纯疱疹病毒1型ICP47蛋白抑制具有抗性的TAP2蛋白变体。

Identification of TAP2 protein variants resistant to inhibition by the HSV1 ICP47 protein.

作者信息

Nagy Gregory, Presley Rebecca, Dhar Shruti, Jeon Hyeongseon, Moreira Lynn, Tull Olivia, Gupta Arkobrato, Chung Dongjun, Tsichlis Philip N, Parvin Jeffrey D

机构信息

Department of Biomedical Informatics and the OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH.

Department of Cancer Biology & Genetics and the OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH.

出版信息

bioRxiv. 2024 Nov 18:2024.11.18.624061. doi: 10.1101/2024.11.18.624061.

DOI:10.1101/2024.11.18.624061
PMID:39605359
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11601387/
Abstract

Herpes Simplex Virus 1 evades the host immune system by expressing a protein, ICP47, that binds to and inhibits the heterodimeric Transporter Associated with Antigen Processing (TAP). We screened a library of 1786 variants in TAP2, one of the components of the TAP heterodimer, and identified 39 variants that were resistant to inhibition by ICP47. Of these 39 variants, five were individually tested, and three (T257I, S274H, and T244R) were confirmed to be significantly resistant to inhibition by ICP47. This resistance to inhibition did not extend to the Epstein Barr Virus BNLF2a protein, another viral factor known to inhibit antigen presentation by targeting TAP. These three residues localize close to the binding site of ICP47, on the 3D structure of TAP, but only Ser274 is spatially close to the antigenic peptide binding site of TAP. These results functionally resolve the TAP2 residues required for peptide binding from those required for ICP47 binding and identify TAP2 residues whose targeting with small molecule inhibitors could effectively prevent Herpes virus downregulation of antigen processing.

摘要

单纯疱疹病毒1型通过表达一种名为ICP47的蛋白质来逃避宿主免疫系统，该蛋白质可与抗原加工相关转运体（TAP）异二聚体结合并抑制其功能。我们筛选了TAP异二聚体的组成成分之一TAP2中的1786个变体文库，鉴定出39个对ICP47抑制具有抗性的变体。在这39个变体中，对其中5个进行了单独测试，其中3个（T257I、S274H和T244R）被证实对ICP47的抑制具有显著抗性。这种对抑制的抗性并不延伸至爱泼斯坦-巴尔病毒的BNLF2a蛋白，后者是另一种已知通过靶向TAP来抑制抗原呈递的病毒因子。在TAP的三维结构上，这三个残基位于靠近ICP47结合位点的位置，但只有Ser274在空间上靠近TAP的抗原肽结合位点。这些结果从功能上区分了TAP2中肽结合所需的残基和ICP47结合所需的残基，并确定了用小分子抑制剂靶向这些TAP2残基可有效防止疱疹病毒下调抗原加工。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/430ae581f648/nihpp-2024.11.18.624061v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/b45421ab3db7/nihpp-2024.11.18.624061v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/f56d07981680/nihpp-2024.11.18.624061v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/ac4b1d17902f/nihpp-2024.11.18.624061v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/7589bcc82124/nihpp-2024.11.18.624061v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/430ae581f648/nihpp-2024.11.18.624061v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/b45421ab3db7/nihpp-2024.11.18.624061v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/f56d07981680/nihpp-2024.11.18.624061v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/ac4b1d17902f/nihpp-2024.11.18.624061v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/7589bcc82124/nihpp-2024.11.18.624061v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9286/11601387/430ae581f648/nihpp-2024.11.18.624061v1-f0005.jpg

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