Sustained high expression of multiple APOBEC3 cytidine deaminases in systemic lupus erythematosus

Abstract

APOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.

The implications of APOBEC3-mediated C-to-U RNA editing for human disease

“…5 ). Strong evidence suggests that expression of APOBEC3 enzymes increases in certain tissues when exposed to hypoxia or increased environmental interferons 8 , 12 – 15 . These conditions may be limited in area and duration, as may be observed in acute viral infection; they may also be more widespread and long-lasting, as may be the case in chronic hypoxia resulting from emphysema or widespread inflammation resulting from autoimmunity.…”

“…Here, we have shown evidence that RNA editing could also play a role in creating the variant proteins that contribute to human disease. Previous works have shown that the extent of RNA editing is sensitive to environmental factors such as interferon presence and hypoxia, and, in an era where worries about our changing environment are ever- increasing, understanding how environmentally sensitive mechanisms like RNA editing affect our cells is essential 8 , 12 , 14 , 15 . Future research will apply our analysis to the transcriptomes and proteomes of specific disease conditions in order to further clarify the functional and predictive role of APOBEC-mediated C > U RNA editing in human disease.…”

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

“…A3G inhibits retrovirus replication and the retrotransposition of HERVs [ 65 ]. The A3G and other A3 RNAs were overexpressed in the serum of SLE patients compared to healthy controls [ 66 ] and in the minor salivary glands of patients with Sjogren’s Syndrome lymphoma [ 67 ].…”

Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response

“…Could editing of mtDNA be linked to autoimmune diseases? It has been shown that A3A induction may be correlated with autoimmune diseases such Systemic Lupus Erythematosus (SLE) [44]. Indeed, A3A-induced mtDNA editing could be involved in the pathophysiology of autoimmune diseases, by generating or increasing the autoantigen load, a key requisite for the progression of autoimmunity.…”