Frame-shifted APOBEC3A encodes two alternative proapoptotic proteins that target the mitochondrial network

Abstract

The human APOBEC3A (A3A) cytidine deaminase is a powerful DNA mutator enzyme recognized as a major source of somatic mutations in tumor cell genomes. However, there is a discrepancy between APOBEC3A mRNA levels after interferon stimulation in myeloid cells and A3A detection at the protein level. To understand this difference, we investigated the expression of two novel alternative “A3Alt” proteins encoded in the +1-shifted reading frame of the APOBEC3A gene. A3Alt-L and its shorter isoform A3Alt-S appear to be transmembrane proteins targeted to the mitochondrial compartment that induce membrane depolarization and apoptosis. Thus, the APOBEC3A gene represents a new example wherein a single gene encodes two proapoptotic proteins, A3A cytidine deaminases that target the genome and A3Alt proteins that target mitochondria.

A Conserved uORF Regulates APOBEC3G Translation and Is Targeted by HIV-1 Vif Protein to Repress the Antiviral Factor

“…This behavior is not unusual for A3A/A3B and could be linked to their Vif-induced nucleocytoplasmic transport [ 57 ]. A3A presents two isoforms (A3A-L and A3A-S) due to a leaky scanning mechanism as previously observed [ 56 ]. A3D was not significantly reduced as previously observed [ 58 ].…”

“…We now wondered whether this translational regulation could be extended to other A3 proteins. Thus, we performed 5′- and 3′-RACE (5′-rapid amplification of cDNA ends analysis) from human spleen total RNA with A3B, A3C, A3D, and A3H specific primers ( Table A2 ) in order to identify their 5′- and 3′-UTRs (A3A vector (NM_145699.3) was a generous gift from Dr Vincent Caval, Pasteur Institute, Paris [ 56 ]; A3F (NM_145298.5) and A3G (NM_021822) were available in our lab). After cloning and sequencing of the expression constructs, corresponding full-length mRNA sequences were synthesized (Proteogenix, Schiltigheim, France) and consequently cloned into pCMV vectors ( Figure 2 A).…”