Recurrent Loss of APOBEC3H Activity during Primate Evolution

Garcia, Erin I; Emerman, Michael

doi:10.1101/311878

Cited by 5 publications

(5 citation statements)

References 43 publications

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“…However, the price to pay for this mutator enzyme activity is off-target editing associated with somatic mutations and chromosomal rearrangements in many cancer genomes ( 14 , 21 , 23 , 46 , 47 ). To date, no deletion or inactivation allele has been reported for A3A unlike other APOBEC3 family members ( 28 , 48 ). Accordingly, understanding the regulation of A3A expression is now of major concern, as its expression has also been reported to exert additional effects on cellular physiology, causing cell cycle arrest, apoptosis, as well as tumorigenic ROS production ( 15 , 16 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

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

Caval

Suspène

Khalfi

et al. 2021

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

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

Caval

Suspène

Khalfi

et al. 2021

Journal of Biological Chemistry

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“…Interestingly, loss of A3H activity is not unique to humans, as an evolutionary analysis of A3H in Old World monkeys found that A3H activity has been lost in multiple primate species [38].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, several residues in the putative RNA binding region of Loop 1 were found to influence the antiviral potency of African green monkey and patas monkey A3H, providing further evidence that mutations introduced in this loop are a recurrent evolutionary mechanism that results in a loss of function [38]. It is unknown why these loss of function mutations of A3H arise and become fixed in multiple primate species despite the established importance of this restriction factor in the control of retroviruses.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in human APOBEC3H differentially regulate ubiquitination and antiviral activity

Chesarino

Emerman

2020

Preprint

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The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like human immunodeficiency virus (HIV).APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). Here, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification.Inhibiting ubiquitination by mutating all of the A3H lysines increased expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity, thus separating stabilization from function. On the other hand, the instability and functional deficiencies of haplotype III could be rescued by fusion to haplotype II, supporting a model by which antiviral A3H is actively stabilized through a cytoplasmic retention mechanism. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.

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“…The following day, cells were transfected with 600ng provirus (HIV-1ΔVifΔEnvLuc2, unless otherwise noted), 100ng L-VSV-G, and 400ng pcDNA4/TO.A3.3XFLAG or pcDNA4/TOPO empty vector unless otherwise indicated. 72 hours later, virus was harvested and normalized for virion production using an RT-qPCR assay, as described (41, 42). A volume of virus equivalent to 2000mU/mL of RT were used for infection of SUPT1 cells.…”

Section: Methodsmentioning

confidence: 99%

APOBEC3C tandem domain proteins create super restriction factors against HIV-1

McDonnell

Crawford

Dingens

et al. 2020

Preprint

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AbstractHumans encode proteins, called restriction factors, that inhibit replication of viruses like HIV-1. One family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3, shortened to A3) acts by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A-A3H. These genes either have one or two cytidine deaminase domains and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein results in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that only use a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity, but instead inhibit formation of reverse transcription products which correlates with their ability to form large higher order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein, Vif.ImportanceAs a part of the innate immune system, humans encode proteins that inhibit viruses like HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain, and furthermore, are relatively resistant to the viral antagonist, Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens like HIV.

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Recurrent Loss of APOBEC3H Activity during Primate Evolution

Cited by 5 publications

References 43 publications

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

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

Polymorphisms in human APOBEC3H differentially regulate ubiquitination and antiviral activity

APOBEC3C tandem domain proteins create super restriction factors against HIV-1

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