COMMD1/Murr1 Reinforces HIV-1 Latent Infection through IκB-α Stabilization

Taura, Manabu; Kudo, Eriko; Kariya, Ryusho; Goto, Hiroki; Matsuda, Kouki; Hattori, Shin-ichiro; Vaeteewoottacharn, Kulthida; McDonald, Fiona J.; Suico, Mary Ann; Shuto, Tsuyoshi; Kai, Hirofumi; Okada, Seiji

doi:10.1128/jvi.03105-14

Cited by 18 publications

(23 citation statements)

References 64 publications

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“…NELFA is a component of the NELF complex restricting transcription elongation at the LTR promoter in absence of Tat (Karn and Stoltzfus, 2012). COMMD1 is an HIV-1 restriction factor in primary resting CD4 lymphocytes (Ganesh et al, 2003) and can reinforce HIV-1 latency by attenuating NF-κB signaling in myeloid cells (Taura et al, 2015). Another potential identified upstream regulators, Transforming Growth Factor, Beta Receptor 1 (TGFBR1) is also interesting since the mTOR pathway is a downstream effector of TGF-β signaling and an upstream regulator of actin remodeling.…”

Section: Resultsmentioning

confidence: 99%

The mTOR Complex Controls HIV Latency

Besnard

Hakre

Kampmann

et al. 2016

Cell Host & Microbe

176

197

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SUMMARY A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat as well as via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of, CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.

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Section: Resultsmentioning

confidence: 99%

The mTOR Complex Controls HIV Latency

Besnard

Hakre

Kampmann

et al. 2016

Cell Host & Microbe

176

197

View full text Add to dashboard Cite

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“…Induction of cOMMd1 in HIV-1 latent-infected cells also maintains latent HIV-1 infection. The expression of the cOMMd1 protein and mRNA in HIV-1 latent-infected myeloid cells is stronger than in parental cells (10). However, it remains elusive how cOMMd1 transcription and expression are regulated.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of HIV-1 host factor COMMD1 by the Sp family

et al. 2018

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Copper metabolism Murr1 domain containing 1 (COMMD1) has multiple functions in the regulation of protein stability at the plasma membrane and in the cytoplasm. However, the regulation of COMMD1 transcriptional has remained to be elucidated. In the present study, the 5'‑flanking region (‑1,192/+83 bp) of the human COMMD1 gene was cloned. It was observed that the COMMD1 promoter region contains GC‑rich region that has 7 putative Sp1‑binding sites via in silico analysis. The proximal promoter region at ‑289/+83 bp was required for COMMD1 basal promoter activity by deletion constructs of COMMD1 promoter. Moreover, Sp1 inhibitor, mithramycin A, suppressed basal COMMD1 promoter activity. The Sp1‑binding site (‑11/‑1 bp) in the proximal promoter region was a critical site for COMMD1 gene regulation by Sp1 and Sp3. Sp1 upregulated COMMD1 promoter activity, whereas Sp3 suppressed it. Endogenous Sp1 and Sp3 bound to the proximal promoter region of COMMD1. Taken together, Sp1 constitutively regulates the basal expression of the COMMD1 gene in human epithelial cell lines.

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“…Our data showed that, in addition to activating NF-κB p65 itself, p53 expression assists and is involved in NF-κB p65-driven reactivation of HIV-1 latently infected U1 cells. An increased expression of PARP is required for the activation of NF-κB-dependent target genes, including HIV-1 LTR in reporter constructs; a decreased expression of COMMD1 reinforces HIV-1 latent infection through IκBα stabilization [22].…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that the host-derived factor, COMM Domain-containing protein 1 (COMMD1), is able to reinforce HIV-1 latent infection through IκB-α stabilization in U1 cells, which inhibits HIV-1 replication by blocking NF-κB p65 activities in initiation of HIV-1 transcription [22]. To investigate whether p53 had an effect on expression of COMMD1 protein, U1 cells 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is involved in the maintenance of HIV-1 latency, inhibition of the pathway can reactivate HIV-1 replication from its latent infection [18].…”

Section: P53 Expression Suppressed Commd1 Expression and Promoted Parmentioning

confidence: 99%