A G1‐like state allows
            <scp>HIV</scp>
            ‐1 to bypass
            <scp>SAMHD</scp>
            1 restriction in macrophages

Mlčochová, Petra; Sutherland, Katherine A.; Watters, Sarah A.; Bertoli, Cosetta; Bruin, Robertus A.M. de; Rehwinkel, Jan; Neil, Stuart J. D.; Lenzi, Gina M.; Kim, Baek Hui; Khwaja, Asim; Gage, Matthew; Georgiou, Christiana; Chittka, Alexandra; Yona, Simon; Noursadeghi, Mahdad; Towers, Greg J.; Rk, Gupta

doi:10.15252/embj.201696025

Cited by 85 publications

(147 citation statements)

References 60 publications

(73 reference statements)

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“…To test this, we treated MDM with 5 μM ETO, infected cells with HIV‐1 and assayed phosphorylation of SAMHD1 at T592 by immunoblot (Fig A–C). We found that SAMHD1 is phosphorylated in untreated MDM allowing efficient HIV infection, confirming previous data (Mlcochova et al , ). Addition of ETO led to loss of SAMHD1 phosphorylation and reduced HIV‐1 infectivity.…”

Section: Resultssupporting

confidence: 92%

“…In the absence of type I IFN related changes we were able to demonstrate that the ETO‐induced block is mediated by SAMHD1 T592 phosphorylation. Activation of p53 and the downstream p21 lead to decreased expression of CDK1, the key kinase in SAMHD1 phosphorylation (Cribier et al , ; Mlcochova et al , ). As expected from our previous data this loss of CDK1 activity and SAMHD1 phosphorylation was associated with transition of G1‐like MDM back into G0 state without induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…SAMHD1 is a deoxynucleotide triphosphohydrolase (Goldstone et al , ), and the mechanism of HIV restriction is thought to be via depletion of dNTPs to levels that are insufficient for completion of retroviral reverse transcription (RT) (Goldstone et al , ; Lahouassa et al , ; Schmidt et al , ). The activity of SAMHD1 is thought to be regulated by CDK1/2‐mediated phosphorylation at amino acid T592 (Cribier et al , ; White et al , ; Antonucci et al , ; Mlcochova et al , ). Here, we link DNA damage in primary myeloid cells and cellular SAMHD1 activation, in the absence of a type I interferon response.…”

Section: Introductionmentioning

confidence: 99%

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DNA damage induced by topoisomerase inhibitors activates SAMHD 1 and blocks HIV ‐1 infection of macrophages

et al. 2017

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We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV‐1 infection in human monocyte‐derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of cellular dNTPs but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1‐like state. We report that SAMHD1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels. Suppression of infection occurred after completion of viral DNA synthesis, at the step of 2LTR circle and provirus formation. The ETO‐induced block was completely rescued by depletion of SAMHD1 in MDM. Concordantly, infection by HIV‐2 and SIVsm encoding the SAMHD1 antagonist Vpx was insensitive to ETO treatment. The mechanism of DNA damage‐induced blockade of HIV‐1 infection involved activation of p53, p21, decrease in CDK1 expression, and SAMHD1 dephosphorylation. Therefore, topoisomerase inhibitors regulate SAMHD1 and HIV permissivity at a post‐RT step, revealing a mechanism by which the HIV‐1 reservoir may be limited by chemotherapeutic drugs.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA damage induced by topoisomerase inhibitors activates SAMHD 1 and blocks HIV ‐1 infection of macrophages

et al. 2017

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“…Phosphorylation of the enzyme is mediated by the presence of a putative cyclin-binding motif located in the HD domain (residues 450–455), as well as a bipartite cyclinA2-CDK complex binding motif located in the C-terminus (99, 118). Further investigation of this regulatory axis reveals that SAMHD1 phosphorylation likely occurs as cells emerge from a G 0 /quiescent state and transition through G 1 facilitated by a mitogen induced activation of the Raf/MEK/Erk kinase cascade (122). Conversely, for cells residing in a non-cycling G 0 /quiescent state, multiple studies report that the dephosphorylated SAMHD1 species predominates and corresponds with reduced dNTP levels (98, 99, 117).…”

Section: Samhd1 Cellular Regulation and Nucleotide Metabolismmentioning

confidence: 99%

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney

Hollis

2018

Autoimmunity

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SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging role as an effector of innate immunity is affirmed by mutations in the SAMHD1 gene that cause the severe autoimmune disease, Aicardi-Goutieres syndrome (AGS) and that are linked to cancer. Additionally, SAMHD1 functions as a restriction factor for retroviruses such as HIV. Here we review the current biochemical and biological properties of the enzyme including its structure, activity, and regulation by post-translational modifications in the context of its cellular function. We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.

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“…21: e47528 | 2020 ª 2019 The Authors cells using shRNA(Fig EV1A)or full knockout cells using the CRISP-Cas9 technology (CRISP-Cas9-TRIM21,…”

mentioning

confidence: 99%

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Chen

Wang

et al. 2019

EMBO Reports

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SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

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A G1‐like state allows HIV ‐1 to bypass SAMHD 1 restriction in macrophages

Cited by 85 publications

References 60 publications

DNA damage induced by topoisomerase inhibitors activates SAMHD 1 and blocks HIV ‐1 infection of macrophages

DNA damage induced by topoisomerase inhibitors activates SAMHD 1 and blocks HIV ‐1 infection of macrophages

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

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