scholarly journals Mitochondrial hypoxic stress induces widespread RNA editing by APOBEC3G in lymphocyte

2018 ◽  
Author(s):  
Shraddha Sharma ◽  
Jianmin Wang ◽  
Scott Portwood ◽  
Eduardo Cortes-Gomez ◽  
Orla Maguire ◽  
...  
Keyword(s):  
T Cells ◽  
Rna Editing ◽  
De Novo ◽  
Cytidine Deaminase ◽  
Mrna Translation ◽  
Hypoxic Stress ◽  
Mrna Editing ◽  
Metabolic Remodeling ◽  
Editing Enzyme ◽  
Normal Health

AbstractProtein recoding by RNA editing is required for normal health and evolutionary adaptation. However, de novo induction of RNA editing in response to environmental factors is an uncommon phenomenon. While APOBEC3A edits many mRNAs in monocytes/macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Here we show that the related APOBEC3G cytidine deaminase induces site-specific C-to-U RNA editing in natural killer (NK), CD8+ T cells and lymphoma cell lines upon cellular crowding and hypoxia. RNASeq analysis of hypoxic NK cells reveals widespread C-to-U recoding mRNA editing that is enriched for genes involved in mRNA translation. APOBEC3G promotes Warburg-like metabolic remodeling and reduces proliferation of HuT78 T cells under similar conditions. Hypoxia-induced RNA editing by APOBEC3G can be mimicked by the inhibition of mitochondrial respiration, and occurs independently of HIF-1α. Thus, APOBEC3G is an endogenous RNA editing enzyme, which is induced by mitochondrial hypoxic stress to promote adaptation in lymphocytes.

scholarly journals Mutational analysis of apolipoprotein B mRNA editing enzyme (APOBEC1): structure–function relationships of RNA editing and dimerization

1999 ◽  
Vol 40 (4) ◽  
pp. 623-635 ◽  
Author(s):  
Ba-Bie Teng ◽  
Scott Ochsner ◽  
Qian Zhang ◽  
Kizhake V. Soman ◽  
Paul P. Lau ◽  
...  
Keyword(s):  
Structure Function ◽  
Rna Editing ◽  
Apolipoprotein B ◽  
Mutational Analysis ◽  
Mrna Editing ◽  
Editing Enzyme

scholarly journals CCR6 ligands inhibit HIV by inducing APOBEC3G

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1564-1571 ◽  
Author(s):  
Mark K. Lafferty ◽  
Lingling Sun ◽  
Leon DeMasi ◽  
Wuyuan Lu ◽  
Alfredo Garzino-Demo
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Early Stage ◽  
Intrinsic Immunity ◽  
Mrna Editing ◽  
Host Restriction ◽  
Host Restriction Factor ◽  
Mechanism Of Inhibition ◽  
Editing Enzyme ◽  
Apobec3g Expression

AbstractWe have identified a postentry CCR6-dependent mechanism of inhibition of HIV occurring at an early stage of infection mediated by the induction of the host restriction factor apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G). We observed induction of APOBEC3G expression only in CCR6+ cells but not in cells treated with the G inhibitory (Gi) pathway inhibitor pertussis toxin. CCR6 is highly expressed on peripheral blood CD4+CCR5+ memory T cells and by 2 populations of CD4+ T cells within the gut, α4β7+ and T helper type 17, that have been implicated in cell-to-cell spread of HIV and enhanced restoration of CD4+ T cells within gut-associated lymphoid tissue, respectively. This novel CCR6-mediated mechanism of inhibition allows the identification of pathways that induce intrinsic immunity to HIV, which could be useful in devising novel therapeutics that selectively target CCR6+ cells.

scholarly journals Derepression of MicroRNA-mediated Protein Translation Inhibition by Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-like 3G (APOBEC3G) and Its Family Members

2007 ◽  
Vol 282 (46) ◽  
pp. 33632-33640 ◽  
Author(s):  
Jialing Huang ◽  
Zhihui Liang ◽  
Bin Yang ◽  
Heng Tian ◽  
Jin Ma ◽  
...  
Keyword(s):  
Reporter Gene ◽  
Apolipoprotein B ◽  
Cytidine Deaminase ◽  
Family Members ◽  
Cellular Function ◽  
Luciferase Reporter ◽  
Mrna Editing ◽  
Processing Bodies ◽  
Cytidine Deaminase Activity ◽  
Editing Enzyme

The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) and its fellow cytidine deaminase family members are potent restrictive factors for human immunodeficiency virus type 1 (HIV-1) and many other retroviruses. A3G interacts with a vast spectrum of RNA-binding proteins and is located in processing bodies and stress granules. However, its cellular function remains to be further clarified. Using a luciferase reporter gene and green fluorescent protein reporter gene, we demonstrate that A3G and other APOBEC family members can counteract the inhibition of protein synthesis by various microRNAs (miRNAs) such as mir-10b, mir-16, mir-25, and let-7a. A3G could also enhance the expression level of miRNA-targeted mRNA. Further, A3G facilitated the association of microRNA-targeted mRNA with polysomes rather than with processing bodies. Intriguingly, experiments with a C288A/C291A A3G mutant indicated that this function of A3G is separable from its cytidine deaminase activity. Our findings suggest that the major cellular function of A3G, in addition to inhibiting the mobility of retrotransposons and replication of endogenous retroviruses, is most likely to prevent the decay of miRNA-targeted mRNA in processing bodies.

ARCD-1, an apobec-1-related cytidine deaminase, exerts a dominant negative effect on C to U RNA editing

2001 ◽  
Vol 281 (6) ◽  
pp. C1904-C1916 ◽  
Author(s):  
Shrikant Anant ◽  
Debnath Mukhopadhyay ◽  
Vakadappu Sankaranand ◽  
Susan Kennedy ◽  
Jeffrey O. Henderson ◽  
...  
Keyword(s):  
Rna Editing ◽  
Rna Binding ◽  
Cytidine Deaminase ◽  
Binding Activity ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Mrna Editing ◽  
Apob Mrna

Mammalian apolipoprotein B (apoB) C to U RNA editing is catalyzed by a multicomponent holoenzyme containing a single catalytic subunit, apobec-1. We have characterized an apobec-1 homologue, ARCD-1, located on chromosome 6p21.1, and determined its role in apoB mRNA editing. ARCD-1 mRNA is ubiquitously expressed; phylogenetic analysis reveals it to be a distant member of the RNA editing family. Recombinant ARCD-1 demonstrates cytidine deaminase and apoB RNA binding activity but does not catalyze C to U RNA editing, either in vitro or in vivo. Although not competent itself to mediate deamination of apoB mRNA, ARCD-1 inhibits apobec-1-mediated C to U RNA editing. ARCD-1 interacts and heterodimerizes with both apobec-1 and apobec-1 complementation factor (ACF) and localizes to both the nucleus and cytoplasm of transfected cells. Together, the data suggest that ARCD-1 is a novel cytidine deaminase that interacts with apobec-1 and ACF to inhibit apoB mRNA editing, possibly through interaction with other protein components of the apoB RNA editing holoenzyme.

scholarly journals Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat

2019 ◽  
Vol 116 (6) ◽  
pp. 2282-2289 ◽  
Author(s):  
Manabu Taura ◽  
Eric Song ◽  
Ya-Chi Ho ◽  
Akiko Iwasaki
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Cd4 T Cells ◽  
Terminal Repeat ◽  
Target Cells ◽  
Mrna Editing ◽  
Latently Infected ◽  
Infected Cells ◽  
Editing Enzyme ◽  
Hiv 1

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated “A3A”) in maintaining the latency state within HIV-1–infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5′ long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

scholarly journals Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti–HIV-1 activity

2006 ◽  
Vol 203 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Gang Peng ◽  
Ke Jian Lei ◽  
Wenwen Jin ◽  
Teresa Greenwell-Wild ◽  
Sharon M. Wahl
Keyword(s):  
Cytidine Deaminase ◽  
Intracellular Protein ◽  
Mrna Editing ◽  
Hiv Replication ◽  
Potent Inducer ◽  
Virion Infectivity Factor ◽  
Immunodeficiency Virus ◽  
Editing Enzyme ◽  
Anti Hiv ◽  
Hiv 1

Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G), a cytidine deaminase, is a recently recognized innate intracellular protein with lethal activity against human immunodeficiency virus (HIV). Packaged into progeny virions, APOBEC3G enzymatic activity leads to HIV DNA degradation. As a counterattack, HIV virion infectivity factor (Vif) targets APOBEC3G for proteasomal proteolysis to exclude it from budding virions. Based on the ability of APOBEC3G to antagonize HIV infection, considerable interest hinges on elucidating its mechanism(s) of regulation. In this study, we provide the first evidence that an innate, endogenous host defense factor has the potential to promote APOBEC3G and rebuke the virus-mediated attempt to control its cellular host. We identify interferon (IFN)-α as a potent inducer of APOBEC3G to override HIV Vif neutralization of APOBEC3 proteins that pose a threat to efficient macrophage HIV replication. Our data provide a new dimension by which IFN-α mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication.

scholarly journals RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

2020 ◽  
Author(s):  
Emad Y. Alqassim ◽  
Shraddha Sharma ◽  
Anm Nazmul H. Khan ◽  
Tiffany Emmons ◽  
Eduardo Cortes-Gomez ◽  
...  
Keyword(s):  
Rna Editing ◽  
Cytidine Deaminase ◽  
Macrophage Polarization ◽  
Surface Protein ◽  
Virus Infections ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Surface Protein Expression ◽  
Functional Polarization ◽  
Editing Enzyme

AbstractPro-inflammatory (M1) macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C>U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here, we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections of normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of deleterious C>U RNA editing occurred in THOC5, encoding a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces pro-inflammatory M1 markers including IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis and glycolytic capacity. Thus, APOBEC3A cytidine deaminase plays an important role in transcriptomic and functional polarization of M1 macrophages.

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