The von Hippel–Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases

Scholtés, Gaël K.; Sawyer, Aubrey M.; Vaca, Cristina C.; Clerc, Isabelle; Roh, Meejeon; Cao, Song; D’Aquila, Richard T.

doi:10.1016/j.trsl.2021.05.002

Cited by 6 publications

(6 citation statements)

References 113 publications

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“…A3B protein levels are increased by epoxomicin treatment in mock-, B3-and C2-infected conditions (Fig 7E). These observations are consistent with work by Scholte ´s and colleagues identifying proteasomal activity as a post-translational mechanism regulating the amounts of A3 proteins [27]. We conclude that A3B degradation takes place both in mock-, B3-and C2-infected cells and that this degradation is dependent of the proteasome.…”

Section: Plos Pathogenssupporting

confidence: 93%

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

et al. 2023

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Human adenoviruses (HAdVs) are a large family of DNA viruses counting more than a hundred strains divided into seven species (A to G). HAdVs induce respiratory tract infections, gastroenteritis and conjunctivitis. APOBEC3B is a cytidine deaminase that restricts several DNA viruses. APOBEC3B is also implicated in numerous cancers where it is responsible for the introduction of clustered mutations into the cellular genome. In this study, we demonstrate that APOBEC3B is an adenovirus restriction factor acting through a deaminase-dependent mechanism. APOBEC3B introduces C-to-T clustered mutations into the adenovirus genome. APOBEC3B reduces the propagation of adenoviruses by limiting viral genome replication, progression to late phase, and production of infectious virions. APOBEC3B restriction efficiency varies between adenoviral strains, the A12 strain being more sensitive to APOBEC3B than the B3 or C2 strains. In A12-infected cells, APOBEC3B clusters in the viral replication centers. Importantly, we show that adenovirus infection leads to a reduction of the quantity and/or enzymatic activity of the APOBEC3B protein depending on the strains. The A12 strain seems less able to resist APOBEC3B than the B3 or C2 strains, a characteristic which could explain the strong depletion of the APOBEC3-targeted motifs in the A12 genome. These findings suggest that adenoviruses evolved different mechanisms to antagonize APOBEC3B. Elucidating these mechanisms could benefit the design of cancer treatments. This study also identifies adenoviruses as triggers of the APOBEC3B-mediated innate response. The involvement of certain adenoviral strains in the genesis of the APOBEC3 mutational signature observed in tumors deserves further study.

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Section: Plos Pathogenssupporting

confidence: 93%

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

et al. 2023

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“…Supporting the role of the HIF transcription factor in controlling AID expression, it has been shown that the inactivation of pVHL leads to a strong accumulation of the HIF‐1α protein, and consequently to increased protein levels of the members of the APOBEC3 cytidine deaminase (A3B) family, which includes AID [13]. Thus, we would have expected that inactivation of pVHL would lead to enhanced HIF‐dependent transcriptional activity [13], resulting in increased production of the AID mRNA and protein and more efficient CSR and SHM in a hypoxic environment in the GC or in response to cytokine signaling. Nevertheless, a B‐cell‐specific KO of pVHL, which resulted in constitutive HIF‐1α stabilization [6, 13], surprisingly led to impaired affinity maturation and defective CSR [6].…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we would have expected that inactivation of pVHL would lead to enhanced HIF‐dependent transcriptional activity [13], resulting in increased production of the AID mRNA and protein and more efficient CSR and SHM in a hypoxic environment in the GC or in response to cytokine signaling. Nevertheless, a B‐cell‐specific KO of pVHL, which resulted in constitutive HIF‐1α stabilization [6, 13], surprisingly led to impaired affinity maturation and defective CSR [6]. These results highlight the underlying difficulty of exploring the role of hypoxia and HIF in antibody diversification in vivo.…”

Section: Resultsmentioning

confidence: 99%

Optimal AID expression and efficient immunoglobulin class switch recombination are dependent on the hypoxia‐inducible factor

Heyer

Reina‐San‐Martin

2023

Eur J Immunol

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During immune responses, B cells engaging a cognate antigen are recruited to GCs in secondary lymphoid organs where they will diversify their BCR to generate highly specific and adapted humoral responses. They do so, by inducing the expression of activation‐induced cytidine deaminase (AID), which initiates somatic hypermutation (SHM) and class switch recombination (CSR). AID deaminates cytosines in ss DNA, generating U:G mismatches that are processed to induce ds DNA break intermediates during CSR that result in the expression of a different antibody isotype. Interestingly, hypoxia regions have been reported in GCs and suggesting that hypoxia could modulate the humoral response. Furthermore, hypoxia inducible transcription factor (HIF) can bind to the AID promoter and induce AID expression in a non‐B‐cell setting, suggesting that it might be involved in the transcriptional induction of AID in B cells, hence, regulating SHM and CSR. We, thus, hypothesized that HIF could regulate the efficiency of CSR. Here, we show that the inactivation of both the HIF‐1α and HIF‐1β subunits of the HIF transcription factor in murine CH12 B cells results in defective CSR and that this is due to the suboptimal induction of AID expression.

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“…Human hepatocytes containing UBE2L3 polymorphisms have been found to be more susceptible to hepatitis B viral infection due to increased proteasome-mediated degradation of A3A ( 22 ). Additionally, multiple overexpressed APOBEC3 family members have been shown to be controlled by the activity of ubiquitin ligase complexes containing von Hippel–Lindau tumor suppressor protein (pVHL) and ariadne RING-in-between-RING E3 ubiquitin protein ligase 1 (ARIH1) ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, reduced activity of the F-box protein, FBXO22, contributes to tumor progression and metastasis in lung and breast cancers by increasing levels of key oncogenic factors such as Bach1, HDM2 and SNAIL ( 33 ). Since APOBEC3 protein abundance has been shown to be controlled by proteasome activity in human embryonic kidney cells ( 23 ), somatically acquired alterations in such ubiquitin-proteasome pathway factors may similarly cause changes in A3A protein abundance leading to enhanced cancer cell mutagenesis.…”

Section: Introductionmentioning

confidence: 99%

An impaired ubiquitin-proteasome system increases APOBEC3A abundance

Coxon,

Dennis,

Dananberg

et al. 2023

NAR Cancer

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Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1–cullin–F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.

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The von Hippel–Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases

Cited by 6 publications

References 113 publications

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

Optimal AID expression and efficient immunoglobulin class switch recombination are dependent on the hypoxia‐inducible factor

An impaired ubiquitin-proteasome system increases APOBEC3A abundance

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