Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes
Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes
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DOI：
10.1038/nm.2102
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发表时间：
2010-03-01
期刊：
影响因子：
82.9
通讯作者：
Giacca, Mauro
中科院分区：
文献类型：
--
作者：
Manganaro, Lara;Lusic, Marina;Giacca, Mauro
长期的证据表明，静止的人外周血T淋巴细胞(PBL)不支持有效的HIV感染。在静止的PBL中，病毒RNA的反转录比在激活的细胞中需要更长的时间(1)，部分原因是反转录后期产物的形成被载脂蛋白B mRNA编辑酶催化多肽样3G(APOBEC3G)的RNA结合而减少(2)。在随后的步骤中，最终形成的病毒互补DNA的整合明显受损(3，4)。在这里，我们展示了细胞c-jun氨基末端激酶(JNK)，一种在静止的CD4(+)T细胞中不表达的酶，调节对HIV-1感染的通透性，我们揭示了一种新的，连续的蛋白质修饰后途径，调节病毒DNA整合。我们发现，在活化的T淋巴细胞中，介导HIV-1基因整合到宿主细胞基因组中的病毒整合酶被JNK磷酸化，该酶位于其核心区一个高度保守的丝氨酸残基上。磷酸化的整合酶反过来成为细胞内肽基-Pro-异构酶Pin1的底物，该酶催化整合酶的构象修饰。这些协调一致的活动增加了整合酶的稳定性，是有效整合和感染HIV-1所必需的。缺乏这些修饰限制了病毒在未激活的初级CD4(+)T淋巴细胞中的感染。
Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells(1), partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G)(2). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired(3,4). Here we show that cellular c-Jun N-terminal kinase (JNK), an enzyme that is not expressed in resting CD4(+) T cells, regulates permissiveness to HIV-1 infection, and we unravel a new, sequential post-translational pathway of protein modification that regulates viral DNA integration. We found that, in activated T lymphocytes, viral integrase, which mediates HIV-1 cDNA integration into the host cell genome, is phosphorylated by JNK on a highly conserved serine residue in its core domain. Phosphorylated integrase, in turn, becomes a substrate for the cellular peptidyl prolyl-isomerase enzyme Pin1, which catalyzes a conformational modification of integrase. These concerted activities increase integrase stability and are required for efficient HIV-1 integration and infection. Lack of these modifications restricts viral infection in nonactivated, primary CD4(+) T lymphocytes.