Retroelement inhibition by human APOBEC3 enzymes

The various innate defense mechanisms against parasitic nucleic acids include the enzymes of the APOBEC family (of which AID is a member). Specifically, the APOBEC3 (abbreviated A3) enzymes inhibit the replication of exogenous and endogenous retroelements. However, while there are seven A3 enzyme family members in humans, in mice there is only one, and it is much less efficient. For example, murine A3 does not inhibit MLV, while human A3G does. We have generated autoimmune-prone mice that are transgenic for the human A3 (abbreviated huA3) proteins. Endogenous retroelements, including MLV, ought to be inhibited in these mice, and, therefore, autoimmune disease ought to be ameliorated.

We have generated a huA3 transgenic mouse in a standard strain; this mouse expresses mRNAs encoding all seven human APOBEC3 proteins. We are currently characterizing the adaptive immune system of this mouse and probing its ability to inhibit retroelement activity. We have also bred it onto a Trex1-minus background. Trex1-deficient mice develop myocarditis and glomerulonephritis. In the absence of this enzyme, cDNA accumulates, triggering the innate interferon type I stimulatory DNA response. In the Trex1-deficient mice, the huA3 ought to prevent retroelement cDNA from accumulating and thus ought to ameliorate autoimmune disease.

We have also generated NZW mice with the huA3. The F1 generation of NZB and NZW mice (B/W mice) have long been studied as a standard model for lupus disease. These mice produce high titers of endogenous MLV, which ought to be suppressed by human A3. We are now analyzing the propensity of the transgenic B/W mice for autoimmune disease.

In collaboration with Drs. Hans-Martin Jäck and Rebecca Winkelmann, University of Erlangen-Nuremberg; and Dr. Dan Eilat, University of Jerusalem.