HIV-1 Tat Inhibits the 20 S Proteasome and Its 11 S Regulator-mediated Activation

Seeger, Michael; Ferrell, Katherine; Frank, Rainer; Dubiel, Wolfgang

doi:10.1074/jbc.272.13.8145

Cited by 106 publications

(82 citation statements)

References 29 publications

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“…Ad E1A could in¯uence this protein degradation pathway in a number of ways but as an initial study we have considered the possibility that it could be having a direct e ect on proteasomal activity as has recently been reported for the HIV-1 Tat protein (Seeger et al, 1997). We report here that both the Ad5 289 and 243a.a.…”

Section: Introductionsupporting

confidence: 50%

“…For example, HTLV-1 Tax binds to HsN3 and HC9 components of the 20S proteasome potentiating anchorage of NF-kB1/p105 to the proteasome (Rousset et al, 1996). Perhaps more relevantly, HIV-1 Tat inhibits the activity of the 20S proteasome (directed against peptide substrates) but potentiates the activity of 26S (against a ubiquinated protein substrate) (Seeger et al, 1997). HIV-1 Tat also interacts with two proteins (Tat binding proteins TBP-1 and TBP-7) which are homologous to yeast SUG1 and MSS1 but are not identical to mammalian SUG1 (Ohana et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

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Adenovirus early region 1A protein binds to mammalian SUG1-a regulatory component of the proteasome

et al. 1999

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Adenovirus early region 1A (Ad E1A) is a multifunctional protein which is essential for adenovirusmediated transformation and oncogenesis. Whilst E1A is generally considered to exert its in¯uence on recipient cells through regulation of transcription it also increases the level of cellular p53 by increasing the protein halflife. With this in view, we have investigated the relationship of Ad E1A to the proteasome, which is normally responsible for degradation of p53. Here we have shown that both Ad5 and Ad12 E1A 12S and 13S proteins can be co-immunoprecipitated with proteasomes and that the larger Ad12 E1A protein binds strongly to at least three components of the 26S but not 20S proteasome. One of these interacting species has been identi®ed as mammalian SUG1, a proteasome regulatory component which also plays a role in the cell as a mediator of transcription. In vitro assays have demonstrated a direct interaction between Ad12 E1A 13S protein and mouse SUG1. Following infection of human cells with Ad5 wt and Ad5 mutants with lesions in the E1A gene it has been shown that human SUG1 can be co-immunoprecipitated with full-length E1A and with E1A carrying a deletion in conserved region 1 which is the region considered to be responsible for increased expression of p53. We have concluded therefore that Ad E1A binds strongly to SUG1 but that this interaction is not responsible for inhibition of proteasome activity. This is consistent with the observation that puri®ed Ad12 E1A inhibits the activity of the puri®ed 20S but not 26S proteasomes. We have also demonstrated that SUG1 can be co-immunoprecipitated with SV40 T and therefore we suggest that this may represent a common interaction of transforming proteins of DNA tumour viruses.

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Section: Introductionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Adenovirus early region 1A protein binds to mammalian SUG1-a regulatory component of the proteasome

et al. 1999

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“…For example, HIV-1 can increase cellular endocytosis of HLA molecules via nef 45,46 , limit HLA transcription and peptide processing via tat 47,48 and suppress TAP-mediated peptide transport into the endoplasmic reticulum 49 . Under selection pressure from the immune system, HIV-1 also mutates rapidly to evade cytotoxic T lymphocyte responses.…”

Section: Discussionmentioning

confidence: 99%

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Pymm

Illing

Ramarathinam

et al. 2017

Nat Struct Mol Biol

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“…Tat's interaction with Mdm2 is intriguing in view of the role this ubiquitin-ligase plays in the endocytosis and degradation of other cell surface receptors (55)(56)(57). Interestingly, Tat has also been shown to interact with subunits of the proteasome and increase the activity of the 26S proteasome (58,59). In addition to CD127 and RON, Tat has also been shown to induce the proteasomal degradation of microtubule-associated protein 2 (43) and postsynaptic density protein 95 (44).…”

Section: Discussionmentioning

confidence: 99%

Soluble HIV Tat Protein Removes the IL-7 Receptor α-Chain from the Surface of Resting CD8 T Cells and Targets It for Degradation

Faller

Sugden

McVey

et al. 2010

The Journal of Immunology

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IL-7 signaling is essential to CD8 T cell development, activation, and homeostasis. We have previously shown decreased expression of the IL-7R α-chain (CD127) on CD8 T cells in HIV+ patients and that this downregulation is mediated at least in part by the HIV Tat protein. We show in this study that CD127 has a prolonged t1/2 in resting CD8 T cells and continuously recycles on and off the cell membrane. We also demonstrate soluble Tat protein significantly decreases the t1/2 of CD127. Soluble Tat is taken up from the medium and accumulates in CD8 T cells with a peak of 6 h. Once inside the cell, Tat exits the endosomes during their normal acidification and enters the cytosol. Tat then translocates to the inner leaflet of the cell membrane, where it binds directly to the cytoplasmic tail of CD127, inducing receptor aggregation and internalization through a process dependent on microtubules. Tat appears to then target CD127 for degradation via the proteasome. By removing CD127 from the cell surface, the HIV Tat protein is thus able to reduce IL-7 signaling and impair CD8 T cell proliferation and function.

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HIV-1 Tat Inhibits the 20 S Proteasome and Its 11 S Regulator-mediated Activation

Cited by 106 publications

References 29 publications

Adenovirus early region 1A protein binds to mammalian SUG1-a regulatory component of the proteasome

Adenovirus early region 1A protein binds to mammalian SUG1-a regulatory component of the proteasome

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Soluble HIV Tat Protein Removes the IL-7 Receptor α-Chain from the Surface of Resting CD8 T Cells and Targets It for Degradation

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