Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins

Sakuma, Ryuta; Noser, Josh A.; Ohmine, Seiga; Ikeda, Yasuhiro

doi:10.1038/nm1562

Cited by 94 publications

(115 citation statements)

References 30 publications

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“…In addition to their effects on early postentry events, both overexpression of rhesus TRIM5␣ and overexpression of human TRIM5␣ have been reported to specifically inhibit the late-phase production of infectious HIV-1 strains (35,36,50,51), and some (35,51), but not all (50), of these studies have found that inhibiting TRIM5 expression by using siRNA constructs targeting sequences common to all TRIM5 isoforms improves HIV-1 production in cells expressing physiological levels of rhesus or human TRIM5. In this context, Sakuma et al (36) reported that a truncated version of rhesus TRIM5 lacking the SPRY domain retained the ability to inhibit HIV-1 production.…”

Section: Discussionmentioning

confidence: 99%

Modulation of TRIM5α Activity in Human Cells by Alternatively Spliced TRIM5 Isoforms

Battivelli

Migraine

Lecossier

et al. 2011

J Virol

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TRIM5␣ is a restriction factor that can block an early step in the retroviral life cycle by recognizing and causing the disassembly of incoming viral capsids, thereby preventing the completion of reverse transcription. Numerous other isoforms of human TRIM5 exist, and isoforms lacking a C-terminal SPRY domain can inhibit the activity of TRIM5␣. Thus, TRIM5␣ activity in a given cell type could be dependent on the relative proportions of TRIM5 isoforms expressed, but little information concerning the relative expression of TRIM5 isoforms in human cells is available. In this study, we demonstrate that mRNAs coding for TRIM5␣ represent only 50% of total TRIM5 transcripts in human cell lines, CD4 ؉ T cells, and macrophages. Transcripts coding for, in order of abundance, TRIM5 (TRIM5-iota), a previously uncharacterized isoform, TRIM5␥, TRIM5␦, and TRIM5 are also present. Like TRIM5␥ and TRIM5␦, TRIM5 and TRIM5 do not inhibit HIV-1 replication, but both have dominant-negative activity against TRIM5␣. Specific knockdown of TRIM5 increases TRIM5␣ activity in human U373-X4 cells, indicating that physiological levels of expression of truncated TRIM5 isoforms in human cells can reduce the activity of TRIM5␣.Following the entry of retroviral capsids into the cytoplasm of target cells, they can encounter cellular restriction factors that block the early steps of the viral life cycle. One wellcharacterized early restriction factor is TRIM5␣ (22,27,41,46), whose recognition of the incoming capsid leads to rapid capsid disassembly, preventing the completion of reverse transcription (42). Human TRIM5␣ can potently inhibit N-tropic murine leukemia virus (N-MLV) (12,18,31,48) and moderately inhibit equine infectious anemia virus and feline immunodeficiency virus replication (8,18,33). The infectivity of laboratory-adapted strains of HIV-1 is inhibited only 2-to 3-fold by the physiological levels of human TRIM5␣ expressed in human cells (13,17,39,44,49), but HIV-1 expressing capsid proteins derived from clinical isolates can be considerably more sensitive to human TRIM5␣, especially if TRIM5␣ expression in target cells is augmented by pretreatment with alpha interferon (IFN-␣) (1).TRIM5␣ is the longest of numerous TRIM5 isoforms expressed in human cells (Fig. 1) and is composed of several distinct domains. The RING domain (coded by exon 2) expresses E3 ubiquitin ligase activity, is required for optimal antiviral activity, and contributes to the rapid turnover of TRIM5␣ (9,15,41). The function of the B-box 2 domain (coded by exon 2) is not fully understood, but amino acid changes in this region can influence TRIM5␣ turnover, higherorder self-association of TRIM5␣ dimers, the formation of TRIM5␣-containing cytoplasmic bodies, and antiviral activity (7,10,15,20). The coiled-coil domain (coded by exons 2 to 4) promotes the formation of homodimers and participates in capsid recognition (16,19,24,26,30). These three domains comprise the RING/B-box/coiled-coil (RBCC) tripartite motif characteristic of all TRIM proteins. Finally, TRIM5␣ als...

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Section: Discussionmentioning

confidence: 99%

Modulation of TRIM5α Activity in Human Cells by Alternatively Spliced TRIM5 Isoforms

Battivelli

Migraine

Lecossier

et al. 2011

J Virol

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“…They have been shown to participate in numerous distinct processes, including roles in development, both normal and tumorous, asymmetric cell divisions and viral response (Arama et al, 2000;Horn et al, 2004;Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006;Sakuma et al, 2007) and see Table 2 in Meroni and Diez-Roux (2005), to name but a few. This protein superfamily is characterized by the presence of multiple protein-protein interaction domains, from which it has derived its name, that is, RING, B-box, and coiled-coil domains (Fig.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade

O’Farrell

Esfahani

Engström

et al. 2007

Developmental Dynamics

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Drosophila Dappled (DPLD) is a member of the RBCC/TRIM superfamily, a protein family involved in numerous diverse processes such as developmental timing and asymmetric cell divisions. DPLD belongs to the LIN-41 subclade, several members of which are micro RNA (miRNA) regulated. We re-examined the LIN-41 subclade members and their relation to other RBCC/TRIMs and dpld paralogs, and identified a new Drosophila muscle specific RBCC/TRIM: Another B-Box Affiliate, ABBA. In silico predictions of candidate miRNA regulators of dpld identified let-7 as the strongest candidate. Overexpression of dpld led to abnormal eye development, indicating that strict regulation of dpld mRNA levels is crucial for normal eye development. This phenotype was sensitive to let-7 dosage, suggesting let-7 regulation of dpld in the eye disc. A cell-based assay verified let-7 miRNA down-regulation of dpld expression by means of its 3 -untranslated region. Thus, dpld seems also to be miRNA regulated, suggesting that miRNAs represent an ancient mechanism of LIN-41 regulation. Developmental Dynamics 237:196 -208, 2008.

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“…The coiled-coil domain of TRIM5␣ contributes to protein oligomerization and efficient capsid binding and post-entry restriction (10,11). Disruption of the TRIM5␣rh RING domain decreases, but does not eliminate, the restriction of HIV-1 infection (8,12). Although polyubiquitination and rapid degradation of TRIM5␣ depend upon intact RING and B-box 2 domains (13), rapid turnover of TRIM5␣ is not required for its post-entry restriction activity, and proteasome inhibitors cannot prevent the post-entry restriction (9,14).…”

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confidence: 99%

“…In addition to this well characterized post-entry restriction activity, TRIM5␣rh has another "late restriction" activity to affect the production phase of the HIV-1 life cycle (12,18,19). Richardson et al (19) have demonstrated that cellassociated HIV-1 transmission in human cells is blocked only when both donor and recipient cells express TRIM5␣rh.…”

mentioning

confidence: 99%

“…We and others (18,20) have shown that co-expression of the C-terminal hemagglutinin (HA)-tagged TRIM5␣rh with HIV-1 proviral plasmids reduces the yield of infectious virus up to 20 -100-fold, although the late restriction activity of endogenous TRIM5␣rh remains controversial (18,20). High levels of TRIM5␣rh showed potent antiviral activity on HIV-1 production through degradation of Gag polyproteins, whereas modest TRIM5␣rh expression blocks HIV-1 production by reducing the virion infectivity as well as the yield of infectious virus (12,16). When HIV-1 production surpasses the late restriction activity, HIV-1 virions or virus-like particles (VLPs) produced in the presence of TRIM5␣rh protein incorporate high levels of intact and truncated forms of TRIM5␣rh (12,16).…”

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confidence: 99%

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Determinants for the Rhesus Monkey TRIM5α-mediated Block of the Late Phase of HIV-1 Replication

Sakuma

Ohmine

Ikeda

2010

Journal of Biological Chemistry

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Rhesus monkey TRIM5␣ (TRIM5␣rh) includes RING, B-box, coiled-coil, and B30.2(PRYSPRY) domains and blocks HIV-1 infection by targeting HIV-1 core through a B30.2(PRYSPRY) domain. Previously, we reported that TRIM5␣rh also blocks HIV-1 production in a B30.2(PRYSPRY)-independent manner. Efficient encapsidation of TRIM5␣rh, but not human TRIM5␣ (TRIM5␣hu), in HIV-1 virus-like particles suggests the interaction between Gag and TRIM5␣rh during viral assembly. Here, we determined responsible regions for late restriction activity of TRIM5␣rh. The RING disruption, but not the replacement with human TRIM21 RING, ablated the efficient encapsidation and the late restriction, suggesting that a RING structure was essential for the late restriction and efficient interaction with HIV-1 Gag. The prominent cytoplasmic body formation of TRIM5␣rh, which depended on the coiled-coil domain and the ensuing linker 2 region, was not required for the encapsidation. Intriguingly, TRIM5␣rh coiled-coil domain mutants (M133T and/or T146A) showed impaired late restriction activity, despite the efficient encapsidation and cytoplasmic body formation. Our results suggest that the TRIM5␣rh-mediated late restriction involves at least two distinct activities as follows: (i) interaction with HIV-1 Gag polyprotein through the N-terminal, RING, and B-box 2 regions of a TRIM5␣rh monomer, and (ii) an effector function(s) that depends upon the coiled-coil and linker 2 domains of TRIM5␣rh. We speculate that the TRIM5␣rh coiledcoil region recruits additional factor(s), such as other TRIM family proteins or a cellular protease, during the late restriction. RBCC domains of TRIM family proteins may play a role in sensing newly synthesized viral proteins as a part of innate immunity against viral infection.

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Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins

Cited by 94 publications

References 30 publications

Modulation of TRIM5α Activity in Human Cells by Alternatively Spliced TRIM5 Isoforms

Modulation of TRIM5α Activity in Human Cells by Alternatively Spliced TRIM5 Isoforms

Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade

Determinants for the Rhesus Monkey TRIM5α-mediated Block of the Late Phase of HIV-1 Replication

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