Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5

Díaz-Griffero, Felipe; Li, Xing; Javanbakht, Hassan; Song, Byeongwoon; Welikala, Sohanya; Stremlau, Matthew; Sodroski, Joseph

doi:10.1016/j.virol.2005.12.040

Cited by 153 publications

(177 citation statements)

References 52 publications

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“…16,21,22 The proteasome is also involved and causes a decrease in retroviral complementary DNA accumulation in acutely infected cells. 23 TRIM5a proteins can seemingly selfubiquitinate 24,25 and are rapidly degraded by the proteasome on exposure to a restriction-sensitive virus. 26 Finally, TRIM5a interferes with the transport of postentry retroviral complexes toward the nucleus, and this antiviral activity is independent from the one involving the proteasome.…”

Section: Introductionmentioning

confidence: 99%

Generation of human TRIM5α mutants with high HIV-1 restriction activity

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Generation of human TRIM5α mutants with high HIV-1 restriction activity

et al. 2010

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“…In the absence of this information, the relative abundances of the different TRIM5 proteins, which depend on both the rate of transcription and the half-life of each isoform, remain uncertain. Diaz-Griffero et al (9) have shown that following overexpression, TRIM5␣ has a half-life of only 1 h, a property that depends on the RING and B-box 2 domains and not the SPRY domain. Because all TRIM5 isoforms evaluated here share the same RING and B-box 2 domains, this property may be similar for all isoforms, but studies evaluating the turnover of TRIM5 isoforms expressed at physiological levels are required to establish this point.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

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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“…12 There is a pool of rhTRIM5a localized diffusely throughout the cytoplasm, and this pool is capable of exchanging protein with the population of rhTRIM5a that accumulates in puncta throughout the cytoplasm known as cytoplasmic bodies. In addition to rhTRIM5a, heat shock proteins 13 and sequestosome-1/p62 14 have been identified as localizing to cytoplasmic bodies, although these structures likely contain a number of other proteins of which we are not yet aware. Like the well-characterized accumulations of proteins in the nucleus associated with another TRIM family protein called PML, 15,16 cytoplasmic bodies containing rhTRIM5a could also serve as a depot for the recruitment and release of proteins to coordinate the response to cellular stresses such as viral infection.…”

Section: Introductionmentioning

confidence: 99%

“…27,28 rhTRIM5a has been shown to be polyubiquitinated by western blot, and higher levels of polyubiquitinated forms of rhTRIM5a were detected after proteasome inhibition. 13 More relevant to infection is that rhTRIM5a itself undergoes accelerated proteasomal degradation in the presence of restricted virus, 29 revealing that ubiquitination of rhTRIM5a seems to have a functional consequence related to restriction.…”

Section: Introductionmentioning

confidence: 99%

Using Antiubiquitin Antibodies to Probe the Ubiquitination State Within rhTRIM5α Cytoplasmic Bodies

Danielson

Hope

2013

AIDS Research and Human Retroviruses

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The first line of defense protecting rhesus macaques from HIV-1 is the restriction factor rhTRIM5a, which recognizes the capsid core of the virus early after entry and normally blocks infection prior to reverse transcription. Cytoplasmic bodies containing rhTRIM5a have been implicated in the ubiquitin-proteasome pathway, but the specific roles these structures play remain uncharacterized. Here, we examine the ubiquitination status of cytoplasmic body proteins. Using antibodies specific for different forms of ubiquitin, we show that ubiquitinated proteins are present in cytoplasmic bodies, and that this localization is altered after proteasome inhibition. A decrease in polyubiquitinated proteins localizing to cytoplasmic bodies was apparent after 1 h of proteasome inhibition, and greater differences were seen after extended proteasome inhibition. The decrease in polyubiquitin conjugates within cytoplasmic bodies was also observed when deubiquitinating enzymes were inhibited, suggesting that the removal of ubiquitin moieties from polyubiquitinated cytoplasmic body proteins after extended proteasome inhibition is not responsible for this phenomenon. Superresolution structured illumination microscopy revealed finer details of rhTRIM5a cytoplasmic bodies and the polyubiquitin conjugates that localize to these structures. Finally, linkage-specific polyubiquitin antibodies revealed that K48-linked ubiquitin chains localize to rhTRIM5a cytoplasmic bodies, implicating these structures in proteasomal degradation. Differential staining of cytoplasmic bodies seen with different polyubiquitin antibodies suggests that structural changes occur during proteasome inhibition that alter epitope availability. Taken together, it is likely that rhTRIM5a cytoplasmic bodies are involved in recruiting components of the ubiquitin-proteasome system to coordinate proteasomal destruction of a viral or cellular protein(s) during restriction of HIV-1.

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Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5

Cited by 153 publications

References 52 publications

Generation of human TRIM5α mutants with high HIV-1 restriction activity

Generation of human TRIM5α mutants with high HIV-1 restriction activity

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

Using Antiubiquitin Antibodies to Probe the Ubiquitination State Within rhTRIM5α Cytoplasmic Bodies

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