上海巴斯德所發現調控HIV潛伏的重要宿主蛋白

導 讀

潛伏的HIV不能被抗逆轉錄病毒藥物清除，這是當前實現HIV/AIDS根治的主要難點。根治策略的發展亟待潛伏機制的深入研究。2018年5月1日，mbio雜誌在線發表了中國科學院上海巴斯德研究所王建華研究組題為SUN2 modulatesHIV-1 infection and latency through association with lamin A/C to maintain therepressive chromatin的研究論文。研究揭示了宿主蛋白SUN2與核纖層蛋白lamin A/C相互作用通過維持抑制性染色質特性調控HIV的潛伏。

Fig.1SUN2和lamin A/C相互作用調控HIV轉錄和潛伏

研究背景

HIV啟動子LTR（長末端重複）驅動的前病毒DNA轉錄水平的抑制是病毒維持潛伏的關鍵。LTR活性受到宿主因子和病毒本身蛋白的多重調控，其中LTR區域的表觀遺傳學修飾和染色質構象是調控其活性的關鍵因素之一。

宿主蛋白SUN2（Sad, UNC-84 domain protein）是在多種細胞中廣泛表達的二型跨膜蛋白，定位於細胞內層核膜上，與核纖層蛋白Lamin A/C連接，增加細胞骨架的穩定性，在細胞有絲分裂、DNA損傷修復及調控信號通路和基因轉錄中起到重要作用。

結果速覽

研究發現Lamin A/C可把SUN2錨定到HIV-LTR的Nuc（核小體）-1和Nuc-2區域，該區域是LTR驅動轉錄的關鍵調控位點；SUN2/Lamin A/C與HIV-LTR的結合，抑制LTR驅動的HIV前病毒基因轉錄的啟始和延伸;機制上，SUN2/Lamin A/C維持了HIV-LTR區域抑制性染色質特性，阻止包括磷酸化的RNA聚合酶II（RNA polymerase II，RNAPII）在內的轉錄因子至LTR啟動子的招募；干涉SUN2表達，發現LTR Nuc-1和Nuc-2組蛋白修飾H3K4me3顯著增加，並發現姐妹染色單體間的距離增加，代表染色質向活躍形式的構象轉換；TNF-α激活潛伏HIV或HIV的感染可使SUN2/Lamin A/C相互作用解離，也反過來證實SUN2/Lamin A/C相互作用對HIV複製抑制和潛伏維持作用，提示SUN2/Lamin A/C結合解離是啟動HIV複製和潛伏再激活的先決條件。

結 語

本項研究發現調控HIV複製和潛伏的重要宿主蛋白，為抗病毒策略設計提供了宿主新靶點。研究受國家基金委、中科院，及科技部艾滋病和病毒性肝炎重大傳染病防治專項等項目的資助，還得到上海巴斯德所金俠研究員、中科院生化細胞所周兆才研究員和焦石副研究員的支持。

ABSTRACT

The postinte grational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5′-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host』s modulation ofHIV-1 transcription and latency. Here we revealed that 「Sad1 and UNC84 domain containing 2」 (SUN2), an inner nuclear membrane protein, maintained the repressive chromatin and inhibited HIV LTR-driven transcription of proviral DNAthrough an association with lamin A/C. Specifically, lamin A/C tethered SUN2 to the nucleosomes 1 and 2 of the HIV-1 5′-LTR to block the initiation and elongation of HIV-1 transcription. SUN2 knockdown converted chromatin to an active formand thus enhanced the phosphorylation of RNA polymerase II and its recruitment to the 5′-LTR HIV-1 proviral DNA, leading to reactivation of HIV-1 from latency. Conversely, the exogenous factors such as tumor necrosis factor alpha(TNF-α) induced reactivation, and the replication of HIV-1 led to thedisassociation between SUN2 and lamin A/C, suggesting that disruption of theassociation between SUN2 and lamin A/C to convert the repressive chromatin tothe active form might be a prerequisite for the initiation of HIV-1 transcription and replication. Together, our findings indicate that SUN2 is anovel chromatin reassembly factor that helps to maintain chromatin in arepressive state and consequently inhibits HIV-1 transcription.

參考文獻：

1. Wei-Wei Sun, Shi Jiao, Li Sun, Zhaocai Zhou, XiaJin, Jian-Hua Wang. SUN2 Modulates HIV-1 Infection and Latency throughAssociation with Lamin A/C To Maintain the Repressive Chromatin.2018 mBio,9(3)e02408-17. doi:10.1128/mBio.02408-171.

2. 上海巴斯德所發現調控HIV潛伏的重要宿主蛋白

http://www.shanghaipasteur.cas.cn/kxyj2016/kxyj_kyjz2016/201805/t20180502_5005381.html

本期編輯：Annabella

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