Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions.
Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions.
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物种特异性 KRAB-ZFP 通过靶向 PBS 区域作为逆转录病毒阻遏物
DOI：
10.1073/pnas.2119415119
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发表时间：
2022-03-15
影响因子：
11.1
通讯作者：
Yang P
中科院分区：
文献类型：
--
作者：
Yang B;Fang L;Gao Q;Xu C;Xu J;Chen ZX;Wang Y;Yang P
逆转录酶通常靶向快速突变的逆转录病毒中相对保守的区域以抑制其复制。其中一个区域称为引物结合位点（PBS），它必须与宿主tRNA互补才能启动逆转录。通过分析内源性逆转录病毒元件，我们发现宿主细胞使用该序列作为靶点来阻断病毒元件的表达。特定类型的锌指蛋白靶向宿主基因组中的PBS，其不仅抑制内源性病毒的转录，而且抑制外源性逆转录病毒与相同PBS的复制。因此，我们的研究揭示了一种策略，寻找宿主限制性因子靶向逆转录病毒。真核生物基因组含有源自古老病毒的染色体整合的序列，例如内源性逆转录病毒（ERV），其占人类基因组的8%。与外源性逆转录病毒一样，ERV保留了许多共同的功能元件，包括转移RNA（tRNA）引物结合位点（PBS）的相应DNA序列，其用于外源性逆转录病毒的逆转录起始。在这里，通过对位于ERV内的PBS基因座的中等规模分析，结合Kruppel相关盒锌指蛋白（KRAB-ZFP）的染色质免疫沉淀测序（ChIP-seq），我们鉴定了特异性结合不同PBS基因座的多种ZFP。其中，我们重点研究了HIV-1所利用的PBS-Lys，并鉴定了其特异性结合蛋白为小鼠ZFP 961和人ZNF 417/ZNF 587。我们发现这些蛋白质不仅抑制ERV的转录，而且抑制逆转录病毒的整合和转录。这些ZFP的破坏使细胞更容易受到HIV-1感染。因此，我们的研究提供了一种方法来确定潜在的宿主因子，靶向逆转录病毒的ERV。
Hosts often target the relatively conserved regions in rapidly mutating retroviruses to inhibit their replication. One of these regions is called a primer binding site (PBS), which has to be complementary to the host tRNA to initiate reverse transcription. By analyzing endogenous retroviral elements, we found that host cells use this sequence as a target in efforts to block the expression of viral elements. A specific type of zinc finger protein targets the PBS in a host genome, which not only inhibits the transcription of endogenous viruses but also inhibits the replication of exogenous retroviruses with the same PBS. Thus, our study sheds light on a strategy for searching for host restriction factors targeting retroviruses. Eukaryotic genomes harbor sequences derived from the chromosomal integration of ancient viruses, such as endogenous retroviruses (ERVs), which comprise 8% of the human genome. Like exogenous retroviruses, ERVs retain many common functional elements, including the corresponding DNA sequences of transfer RNA (tRNA) primer binding sites (PBSs), which are utilized for reverse transcription initiation by exogenous retroviruses. Here, through a medium-scale analysis of PBS loci positioned within ERVs, coupled with chromatin immunoprecipitation sequencing (ChIP-seq) of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), we identified multiple ZFPs that specifically bind to different PBS loci. Among these, we focused on PBS-Lys, which is utilized by HIV-1, and identified its specific binding proteins to be mouse ZFP961 and human ZNF417/ZNF587. We found that these proteins not only repress ERV transcription but also inhibit retrovirus integration and transcription. Disruption of these ZFPs rendered cells more susceptible to HIV-1 infection. Thus, our research provides a methodology for identifying potential host factors that target retroviruses by ERVs.
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影响因子：
3.3
作者：
Gifford RJ;Blomberg J;Coffin JM;Fan H;Heidmann T;Mayer J;Stoye J;Tristem M;Johnson WE
通讯作者：
Johnson WE
DOI：
10.1016/0005-2787(80)90139-2
发表时间：
1980-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
WATERS, LC;MULLIN, BC;POPP, RA
通讯作者：
POPP, RA
影响因子：
64.8
作者：
Wolf, Daniel;Goff, Stephen P.
通讯作者：
Goff, Stephen P.
影响因子：
64.8
作者：
Rowe, Helen M.;Jakobsson, Johan;Trono, Didier
通讯作者：
Trono, Didier
影响因子：
64.8
作者：
Larsen, Kevin P.;Mathiharan, Yamuna Kalyani;Puglisi, Elisabetta Viani
通讯作者：
Puglisi, Elisabetta Viani