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Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

ABSTRACT: We have investigated the function of inositol hexakisphosphate (IP6) and inositol pentakisphosphate (IP5) in the replication of murine leukemia virus (MLV). While IP6 is known to be critical for the life cycle of HIV-1, its significance in MLV remains unexplored. We find that IP6 is indeed important for MLV replication. It significantly enhances endogenous reverse transcription (ERT) in MLV. Additionally, a pelleting-based assay reveals that IP6 can stabilize MLV cores, thereby facilitating ERT. We find that IP5 and IP6 are packaged in MLV particles. However, unlike HIV-1, MLV depends upon the presence of IP6 and IP5 in target cells for successful infection. This IP6/5 requirement for infection is reflected in impaired reverse transcription observed in IP6/5-deficient cell lines. In summary, our findings demonstrate the importance of capsid stabilization by IP6/5 in the replication of diverse retroviruses; we suggest possible reasons for the differences from HIV-1 that we observed in MLV.

SUBMITTER: Biswas B

PROVIDER: S-EPMC10925174 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

Biswas Banhi B Lai Kin Kui KK Bracey Harrison H Datta Siddhartha A K SAK Harvin Demetria D Sowd Gregory A GA Aiken Christopher C Rein Alan A

bioRxiv : the preprint server for biology 20240227

We have investigated the function of inositol hexakisphosphate (IP6) and inositol pentakisphosphate (IP5) in the replication of murine leukemia virus (MLV). While IP6 is known to be critical for the life cycle of HIV-1, its significance in MLV remains unexplored. We find that IP6 is indeed important for MLV replication. It significantly enhances endogenous reverse transcription (ERT) in MLV. Additionally, a pelleting-based assay reveals that IP6 can stabilize MLV cores, thereby facilitating ERT. ...[more]

PMID: 38464197

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Project description:Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a key post-transcriptional modification that regulates RNA splicing, stability, and translation. Dysregulation of ADAR activity caused by mutations in ADAR1 leads to Aicardi-Goutières syndrome (AGS), an autoimmune disorder characterized by aberrant activation of Melanoma differentiation-associated protein 5 (MDA5) by self RNA and excessive type I interferon production. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Here, we show that ADAR1 protein levels and RNA editing activity in mammalian cells critically depend on the cofactor inositol hexakisphosphate (IP6). Using Inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, next-generation sequencing (NGS), and a cell-permeable IP6 prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. In vitro ADAR1 translation and RNA editing assays revealed that IP6 contributes to the folding and full catalytic activity of ADAR1, and that inositol pentakisphosphate (1,3,4,5,6-IP5) can partially substitute IP6 as a cofactor. Molecular dynamics simulations and biochemical analyses identified the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly governs Zn²⁺-ion positioning through interactions with key residues, including K1039 and N907. Notably, the AGS-associated N907S mutation impairs RNA editing, by altering IP6 coordination and introducing more dynamic situation in the hydrogen-bonding network of IP6 and Zn²⁺-ion. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity. Through a network of interactions and the availability of IP6, this may represent a new strategy for therapeutically controlling RNA editing in the disease.

Dataset Information

Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

Publications

Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

Similar Datasets

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