APOBEC3 Proteins in Viral Immunity

Stavrou, Spyridon; Ross, Susan R.

doi:10.4049/jimmunol.1501504

Cited by 147 publications

(138 citation statements)

References 110 publications

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“…The APOBEC3 (A3) sub-branch members are anti-retroviral/retroelement restriction factors thereby also playing an immune function (21, 22); however, in the last few years, a role in cancer initiation has also emerged for the A3 sub-branch of the family, in particular, A3A, A3B (23–32), and more recently A3H haplotype I (33). …”

Section: Importance and Challenges Of Solving Aid/apobec Structuresmentioning

confidence: 99%

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

King

Larijani

2017

Front. Immunol.

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Activation-induced cytidine deaminase (AID) and its relative APOBEC3 cytidine deaminases boost immune response by mutating immune or viral genes. Because of their genome-mutating activities, AID/APOBECs are also drivers of tumorigenesis. Due to highly charged surfaces, extensive non-specific protein–protein/nucleic acid interactions, formation of polydisperse oligomers, and general insolubility, structure elucidation of these proteins by X-ray crystallography and NMR has been challenging. Hence, almost all available AID/APOBEC structures are of mutated and/or truncated versions. In 2015, we reported a functional structure for AID using a combined computational–biochemical approach. In so doing, we described a new regulatory mechanism that is a first for human DNA/RNA-editing enzymes. This mechanism involves dynamic closure of the catalytic pocket. Subsequent X-ray and NMR studies confirmed our discovery by showing that other APOBEC3s also close their catalytic pockets. Here, we highlight catalytic pocket closure as an emerging and important regulatory mechanism of AID/APOBEC3s. We focus on three sub-topics: first, we propose that variable pocket closure rates across AID/APOBEC3s underlie differential activity in immunity and cancer and review supporting evidence. Second, we discuss dynamic pocket closure as an ever-present internal regulator, in contrast to other proposed regulatory mechanisms that involve extrinsic binding partners. Third, we compare the merits of classical approaches of X-ray and NMR, with that of emerging computational–biochemical approaches, for structural elucidation specifically for AID/APOBEC3s.

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Section: Importance and Challenges Of Solving Aid/apobec Structuresmentioning

confidence: 99%

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

King

Larijani

2017

Front. Immunol.

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“…51,208 The first APOBEC3 protein shown to have activity that restricts HIV infection was A3G. 209 Restriction of HIV by APOBEC3s has been reviewed extensively 210–212 and will not be described here in detail.…”

Section: Apobec3 Subfamilymentioning

confidence: 99%

Functions and Malfunctions of Mammalian DNA-Cytosine Deaminases

2016

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The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracil causing base substitutions and strand breaks. They are induced by cytokines produced during the body’s inflammatory response to infections, and help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport. Members of the APOBEC3 subfamily in humans (APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D/E, APOBEC3F, APOBEC3G and APOBEC3H) inhibit infections of viruses such as HIV, HBV and HCV, and retrotransposition of endogenous retroelements through mutagenic and non-mutagenic mechanisms. There is emerging consensus that these enzymes can cause mutations in the cellular genome at replication forks or within transcription bubbles depending on the physiological state of the cell and the phase of the cell cycle during which they are expressed. We describe here the state of knowledge about the structures of these enzymes, regulation of their expression, and both the advantageous and deleterious consequences of this expression including carcinogenesis. We highlight similarities among them and present a holistic view of their regulation and function.

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“…The A3 genes are a key component of the innate immune system in vertebrates that inhibit replication of a variety of retroviruses, endogenous retroelements and DNA viruses (13,14). Recently, the C-to-T hyper-mutagenesis genomic changes in multiple cancers have been attributed to A3A and A3B (15–17).…”

Section: Introductionmentioning

confidence: 99%

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

Menéndez

Nguyen

Snipe

et al. 2017

Molecular Cancer Research

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The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to interferon. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes we show that under stress conditions and immune challenges all A3 genes are direct transcriptional targets of the tumor suppressor p53. While the expression of most A3 genes (including A3C and A3H) was stimulated by activation of p53, treatment with the DNA damaging agent doxorubicin or the p53 stabilizer Nutlin, led to repression of the A3B gene. Furthermore, p53 could enhance interferon type-I induction of A3 genes. Interestingly, overexpression of a group of tumor-associated p53 mutants in TP53-null cancer cells promoted A3B expression. These findings establish that the “guardian of the genome” role ascribed to p53 also extends to a unique component of the immune system–the A3 genes–thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis.

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APOBEC3 Proteins in Viral Immunity

Cited by 147 publications

References 110 publications

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

Functions and Malfunctions of Mammalian DNA-Cytosine Deaminases

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

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