Abstract
LINE-1 (abbreviated L1) is a major class of retroelements in humans and mice. If unrestricted, retroelements accumulate in the cytoplasm and insert their DNA into the host genome, with the potential to cause autoimmune disease and cancer. Retroviruses and other retroelements are inhibited by proteins of the APOBEC family, of which activation-induced cytidine deaminase (AID) is a member. Although AID is mainly known for being a DNA mutator shaping the antibody repertoire in B lymphocytes, we found that AID also restricts de novo L1 integrations in B- and non-B-cell lines. It does so by decreasing the protein level of open reading frame 1 (ORF1) of both exogenous and endogenous L1. In activated B lymphocytes, AID deficiency increased L1 mRNA 1.6-fold and murine leukemia virus (MLV) mRNA 2.7-fold. In cell lines and activated B lymphocytes, AID forms cytoplasmic high-molecular-mass complexes with L1 mRNA, which may contribute to L1 restriction. Because AID-deficient activated B lymphocytes do not express ORF1 protein, we suggest that ORF1 protein expression is inhibited by additional restriction factors in these cells. The greater increase in MLV compared to L1 mRNA in AID-deficient activated B lymphocytes may indicate less strict surveillance of retrovirus.
Highlights
Activation-induced cytidine deaminase (AID) is a mutator in B lymphocytes that deaminates cytosine to uracil in DNA [1]
We set out to confirm these findings and to extend them to more physiological conditions in a B lymphocyte line, since B cells are the primary site of AID expression
AID is known for its function in adaptive immunity by mutating the Ig locus in activated B lymphocytes and, thereby, generating the secondary antibody repertoire
Summary
Activation-induced cytidine deaminase (AID) is a mutator in B lymphocytes that deaminates cytosine to uracil in DNA [1]. The classic function of AID is to mediate somatic hypermutation and class switch recombination of immunoglobulin (Ig) genes in antigen-stimulated B cells – processes important for the generation of highly specific antibodies with various effector functions [2]. This function is not nearly as exclusive as previously thought. In addition to the Ig locus, AID mutates other loci throughout the genome [3,4]. AID is thought to be critical in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency [5], and AID is required for DNA demethylation and initiation of nuclear reprogramming toward pluripotency in human somatic cells [6]
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