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

Vincent Caval,Rodolphe Suspène,Pierre Khalfi,Julien Gaillard,Grégory Caignard,Damien Vitour,Philippe Roingeard,Jean-Pierre Vartanian,Simon Wain-Hobson

doi:10.1016/j.jbc.2021.101081

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.

Highlights

Oncogenesis, since this enzyme is known to be upregulated through interferon (IFN) signaling in response to many cellular stress [12, 24,25,26], further emphasizing the longstanding observation that cancer emerges on a background of chronic inflammation [27]
A3A-30UTR contributes to reducing A3A expression, since its substitution by A3B-30UTR in the context of a prevalent A3B deletion allele (ΔA3B) [28] results in increased A3A levels and nuclear deoxyribonucleic acid (DNA) damages [13], in keeping with the overrepresentation of APOBEC mutations in the cancer genomes of ΔA3B patients [18]
The AUGs initiation codons S1 and S2 respectively governing the expression of A3A-L and A3A-S cytidine deaminases in A3A messenger ribonucleic acid (RNA) (mRNA) are only present in an “adequate” Kozak context, compatible with leaky scanning

Summary

Introduction

Oncogenesis, since this enzyme is known to be upregulated through interferon (IFN) signaling in response to many cellular stress [12, 24,25,26], further emphasizing the longstanding observation that cancer emerges on a background of chronic inflammation [27]. In keeping with previous studies, A3A cytidine deaminase coding sequence driven by its natural “adequate” Kozak sequence (A3A-L adequate) resulted in the translation of the two functionally active isoforms A3A-L and A3A-S, while only A3A-L was detectable when cloned downstream of the strong Kozak initiation context of pcDNA3.1 expression plasmid (A3A-L strong) (Fig. 1E).

Results

Conclusion