Chatterji Udayan, Bobardt Michael D, Gaskill Peter, Sheeter Dennis, Fox Howard, Gallay Philippe A
Departments of Immunology, Molecular and Integrative Neurosciences, and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
J Biol Chem. 2006 Dec 1;281(48):37025-33. doi: 10.1074/jbc.M606066200. Epub 2006 Oct 6.
The TRIM5alpha (tripartite motif 5alpha protein) has been linked to the cross-species restriction in human immunodeficiency virus type 1 (HIV-1) infection of non-human cells, but the mechanism by which this occurs remains to be fully elucidated. Here we demonstrate that the capsid (CA) protein of HIV-1 is more rapidly degraded in cells expressing monkey TRIM5alpha than in cells expressing human TRIM5alpha. Other proteins encoded by Gag and Pol are not subject to TRIM5alpha-mediated accelerated degradation. The accelerated CA degradation by TRIM5alpha apparently occurs via a nonproteosomal pathway. TRIM5alpha selectively accelerates degradation of the CA population, which reached the cytosol of restrictive cells, but not the CA population, which ended into the vesicular compartment. Given that cytosolic CA represents "productively" entered cores, whereas vesicular CA represents "nonproductively" entered cores, our findings suggest that TRIM5alpha interrupts the infectious pathway of HIV-1 by acting on the incoming cytosolic CA. The mode of viral entry does not influence the accelerated degradation of cytosolic CA by TRIM5alpha. Thus, this study reveals a correlation between TRIM5alpha-mediated HIV-1 restriction and a selective degradation of cytosolic CA normally associated with productive viral entry.
TRIM5α（三聚基序5α蛋白）与人类免疫缺陷病毒1型（HIV-1）感染非人类细胞的跨物种限制有关，但其发生机制仍有待充分阐明。在此，我们证明HIV-1的衣壳（CA）蛋白在表达猴TRIM5α的细胞中比在表达人类TRIM5α的细胞中降解得更快。由Gag和Pol编码的其他蛋白不受TRIM5α介导的加速降解影响。TRIM5α介导的CA加速降解显然是通过非蛋白酶体途径发生的。TRIM5α选择性地加速了到达限制细胞胞质溶胶的CA群体的降解，但没有加速进入囊泡区室的CA群体的降解。鉴于胞质CA代表“有效”进入的核心，而囊泡CA代表“无效”进入的核心，我们的研究结果表明TRIM5α通过作用于进入的胞质CA来中断HIV-1的感染途径。病毒进入模式不影响TRIM5α对胞质CA的加速降解。因此，本研究揭示了TRIM5α介导的HIV-1限制与通常与有效病毒进入相关的胞质CA选择性降解之间的相关性。
