Regulation of protein phosphatase 1γ activity in hypoxia through increased interaction with NIPP1: Implications for cellular metabolism

Comerford, Kathrina M.; Leonard, Martin O.; Cummins, Eoin P.; Fitzgerald, Kathleen T.; Beullens, Monique; Taylor, Cormac T.

doi:10.1002/jcp.20726

Cited by 20 publications

(13 citation statements)

References 33 publications

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“…7,56–58 Previously, PP1 has been shown to be negatively affected by hypoxia either through a decrease of mRNA expression 59 or by increased association with nuclear inhibitor of PP1 (NIPP1). 60 Thus, hypoxia-mediated PP1 inhibition may lead to changes in CDK9 phosphorylation and modulation of its activity. Hypoxia can also modulate the activity of CDK2 through the expression of p27, 61 which may also have a downstream effect on CDK9.…”

Section: Discussionmentioning

confidence: 99%

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Kumari¹,

Ammosova²,

Diaz³

et al. 2016

Blood Advances

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The low incidence of HIV-1 infection in patients with sickle cell disease (SCD) and inhibition of HIV-1 replication in vitro under the conditions of low intracellular iron or heme treatment suggests a potential restriction of HIV-1 infection in SCD. We investigated HIV-1 ex vivo infection of SCD peripheral blood mononuclear cells (PBMCs) and found that HIV-1 replication was inhibited at the level of reverse transcription (RT) and transcription. We observed increased expression of heme and iron-regulated genes, previously shown to inhibit HIV-1, including ferroportin, IKBα, HO-1, p21, and SAM domain and HD domain-containing protein 1 (SAMHD1). HIV-1 inhibition was less pronounced in hepcidin-treated SCD PBMCs and more pronounced in the iron or iron chelators treated, suggesting a key role of iron metabolism. In SCD PBMCs, labile iron levels were reduced and protein levels of ferroportin, HIF-1α, IKBα, and HO-1 were increased. Hemin treatment induced ferroportin expression and inhibited HIV-1 in THP-1 cells, mimicking the HIV-1 inhibition in SCD PBMCs, especially as hepcidin similarly prevented HIV-1 inhibition. In THP-1 cells with knocked down ferroportin, IKBα, or HO-1 genes but not HIF-1α or p21, HIV-1 was not inhibited by hemin. Activity of SAMHD1-regulatory CDK2 was decreased, and SAMHD1 phosphorylation was reduced in SCD PBMCs and hemin-treated THP-1 cells, suggesting SAMHD1-mediated HIV-1 restriction in SCD. Our findings point to ferroportin as a trigger of HIV-1 restriction in SCD settings, linking reduced intracellular iron levels to the inhibition of CDK2 activity, reduction of SAMHD1 phosphorylation, increased IKBα expression, and inhibition of HIV-1 RT and transcription.

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Section: Discussionmentioning

confidence: 99%

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Kumari¹,

Ammosova²,

Diaz³

et al. 2016

Blood Advances

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show abstract

“…Phosphorylation can be fine-tuned by competing dephosphorylations carried out by protein phosphatases. The primary phosphatases that dephosphorylate these residues are PP1 and PP2A [32] [33] [34] [35]. PP1 and PP2A consist of multimeric structures including a catalytic subunit complexed to a number of accessory subunits that are able to regulate the activity of catalytic subunit.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice☆

Shi

Pestka

2009

The Journal of Nutritional Biochemistry

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Consumption of the trichothecene mycotoxin deoxynivalenol (DON) induces interleukin-6 (IL-6)-dependent IgA nephropathy (IgAN) in mice. This effect can be prevented by feeding long chain n-3 polyunsaturated fatty acids (PUFAs) found in fish oil. The purpose of this study was to identify the signal transduction pathways by which DON upregulates IL-6 in the peritoneal macrophage and how consumption of fish oil enriched with the n-3 PUFA, docosahexaenoic acid (DHA), suppresses these processes. Incubation with DON induced IL-6 expression in naïve macrophages maximally at 3 h. Knockdown of the transcription factor cAMP response element-binding protein (CREB) or pharmacologic inhibition of the CREB kinases, Akt1/2, MSK1 and RSK1, downregulated this expression. Inhibition of double-stranded RNA-activated protein kinase (PKR) suppressed not only IL-6 expression but also phosphorylation of CREB and its upstream kinases, Akt1, MSK1 and RSK1. Phosphorylations of PKR, CREB kinases and CREB were markedly impaired in peritoneal macrophages isolated from mice that consumed DHA-enriched fish oil for 6 to 8 wk. DHA’s effects were not explainable by increased activity of protein phosphatase 1 and 2A since both were suppressed in mice consuming the DHA diet. Although cells cultured directly with DHA expressed less IL-6 compared to cells cultured with arachidonic acid (AA), neither fatty acid treatment affected DON-induced protein phosphorylation. Furthermore, DHA and AA similarly inhibited cell-free protein kinase activity. These data suggest that DON-induced IL-6 expression is CREB-mediated and PKR-dependent and that requisite kinase activities for these pathways were suppressed in macrophages from mice fed DHA for an extended period.

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“…Previously, PP1 has been shown to be negatively affected by hypoxia either through a decrease of mRNA expression [102] or increased association with its regulatory subunit, nuclear inhibitor of PP1 [103]. Thus, PP1 inhibition may lead to changes in CDK9 phosphorylation and modulation of its activity.…”

Section: Effect Of Hypoxia On Hiv-1mentioning

confidence: 99%

Role of Cellular Iron and Oxygen in the Regulation of HIV-1 Infection

2013

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Despite efficient antiretroviral therapy, eradication of HIV-1 infection is challenging and requires novel biological insights and therapeutic strategies. Among other physiological and environmental factors, intracellular iron greatly affects HIV-1 replication. Higher iron stores were shown to be associated with faster progression of HIV-1 infection and to inversely correlate with the survival of HIV-1 infected patients. Iron is required for several steps in the HIV-1 life cycle, including reverse transcription, HIV-1 gene expression and capsid assembly. Here, the authors present a comprehensive review of the molecular mechanisms involved in iron- and oxygen-mediated regulation of HIV-1 replication. We also propose key intracellular pathways that may be involved in regulating HIV-1 replication, via protein kinase complexes, CDK9/cyclin T1 and CDK 2/cyclin E, protein phosphatase-1 and other host factors.

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Regulation of protein phosphatase 1γ activity in hypoxia through increased interaction with NIPP1: Implications for cellular metabolism

Cited by 20 publications

References 33 publications

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice☆

Role of Cellular Iron and Oxygen in the Regulation of HIV-1 Infection

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