Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease
| Autor: | Daniel J. Salamango, Adam Z. Cheng, Nadine M. Shaban, Jeongsik Yong, Jennifer L. McCann, William L. Brown, Terumasa Ikeda, Diako Ebrahimi, Reuben S. Harris, Gabriel J. Starrett, Michael A. Carpenter, Jairam R. Lingappa, Christopher M. Richards, Jordan T. Becker, Jiayi Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Science medicine.medical_treatment General Physics and Astronomy Virus Replication Polymorphism Single Nucleotide Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Retrovirus HIV Protease HIV-1 protease Aminohydrolases Sequence Homology Nucleic Acid vif Gene Products Human Immunodeficiency Virus medicine Humans Amino Acid Sequence lcsh:Science Genetics Multidisciplinary Protease Base Sequence Sequence Homology Amino Acid biology Haplotype Cytosine deaminase Alternative splicing General Chemistry biology.organism_classification 3. Good health Isoenzymes Alternative Splicing HEK293 Cells 030104 developmental biology Haplotypes chemistry RNA splicing HIV-1 biology.protein lcsh:Q DNA |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-06594-3 |
| Popis: | Human APOBEC3H (A3H) is a single-stranded DNA cytosine deaminase that inhibits HIV-1. Seven haplotypes (I–VII) and four splice variants (SV154/182/183/200) with differing antiviral activities and geographic distributions have been described, but the genetic and mechanistic basis for variant expression and function remains unclear. Using a combined bioinformatic/experimental analysis, we find that SV200 expression is specific to haplotype II, which is primarily found in sub-Saharan Africa. The underlying genetic mechanism for differential mRNA splicing is an ancient intronic deletion [del(ctc)] within A3H haplotype II sequence. We show that SV200 is at least fourfold more HIV-1 restrictive than other A3H splice variants. To counteract this elevated antiviral activity, HIV-1 protease cleaves SV200 into a shorter, less restrictive isoform. Our analyses indicate that, in addition to Vif-mediated degradation, HIV-1 may use protease as a counter-defense mechanism against A3H in >80% of sub-Saharan African populations. Human APOBEC3H has several haplotypes and splice variants with distinct anti-HIV-1 activities, but the genetics underlying the expression of these variants are unclear. Here, the authors identify an intronic deletion in A3H haplotype II resulting in production of the most active splice variant, which is counteracted by HIV-1 protease. |
| Databáze: | OpenAIRE |
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