Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import.
Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import.
复制标题
DOI：
10.1186/1742-4690-8-104
复制
发表时间：
2011-12-16
期刊：
影响因子：
3.3
通讯作者：
Emiliani S
中科院分区：
文献类型：
--
作者：
Cribier A;Ségéral E;Delelis O;Parissi V;Simon A;Ruff M;Benarous R;Emiliani S
人类免疫缺陷病毒1型(HIV-1)整合到宿主细胞染色体中是病毒整合酶(IN)控制下的重要步骤。虽然这种酶在体外是催化整合反应的必要条件和充分条件，但体内的细胞辅助因子参与了这一过程。染色质相关因子LEDGF/p75与IN相互作用，促进与宿主基因组转录单位的整合。HIV-1IN还与核粘蛋白TNPO3结合，但这种相互作用在病毒复制过程中的意义仍有待探索。在这里，我们提供了对LEDGF/p75和TNPO3相互作用受损的IN突变体的功能分析。其中，先前发现LEDGF/p75相互作用缺乏的IN W131A和IN Q168L也部分受损了与TNPO3的结合。我们观察到，突变取消IN形成四聚体的能力导致LEDGF/p75结合严重减少。与之形成鲜明对比的是，IN的多聚化能力与TnPO3的相互作用之间没有发现相关性。大多数突变病毒在整合步骤中基本上受损，而反映病毒DNA核输入的2-LTR环的数量没有受到显著影响。我们对HIV-1 IN突变体的功能分析揭示了TNPO3相互作用的明显结构基础，并表明IN和TNPO3之间的相互作用不是核进口的主要决定因素，但可能发生在整合之前的核步骤。
Integration of human immunodeficiency virus type 1 (HIV-1) into a host cell chromosome is an essential step under the control of the viral integrase (IN). Although this enzyme is necessary and sufficient to catalyze the integration reaction in vitro, cellular cofactors are involved in the process in vivo. The chromatin-associated factor LEDGF/p75 interacts with IN and promotes integration to transcription units of the host genome. HIV-1 IN also binds the karyopherin TNPO3, however the significance of this interaction during viral replication remains to be explored. Here we present a functional analysis of IN mutants impaired for LEDGF/p75 and TNPO3 interaction. Among them, IN W131A and IN Q168L, that were previously identified to be deficient for LEDGF/p75 interaction, were also partially impaired for TNPO3 binding. We observed that mutations abolishing IN ability to form tetramers resulted in a severe reduction in LEDGF/p75 binding. In sharp contrast, no correlation could be found between the ability of IN to multimerize and TNPO3 interaction. Most of the mutant viruses were essentially impaired for the integration step whereas the amount of 2-LTR circles, reflecting the nuclear import of the viral DNA, was not significantly affected. Our functional analysis of HIV-1 IN mutants reveals distinct structural basis for TNPO3 interaction and suggests that the interaction between IN and TNPO3 is not a major determinant of nuclear import but could take place at a nuclear step prior to integration.
登录
查看更多内容
影响因子：
5.4
作者：
Brussel, A;Sonigo, P
通讯作者：
Sonigo, P
影响因子：
4.8
作者：
Cherepanov, P;Maertens, G;Debyser, Z
通讯作者：
Debyser, Z
DOI：
10.1073/pnas.87.11.4164
发表时间：
1990-06-01
影响因子：
11.1
作者：
FARNET, CM;HASELTINE, WA
通讯作者：
HASELTINE, WA
DOI：
10.1073/pnas.90.13.6125
发表时间：
1993-07-01
影响因子：
11.1
作者：
BUKRINSKY, MI;SHAROVA, N;STEVENSON, M
通讯作者：
STEVENSON, M
影响因子：
5.4
作者：
FARNET, CM;HASELTINE, WA
通讯作者：
HASELTINE, WA