HIV-1 Nef-POTEE; A novel interaction modulates macrophage dissemination via mTORC2 signaling pathway
Autor: | Raj Kamal Tripathi, Monika Sachdev, Umeshkumar Vekariya, Saurabh Kumar Agnihotri, Poonam Singh, Aamir Nazir, Reshu Saxena, Supinder Kaur, Rekha Sachan, Sushila Kumari, Smrati Bhadauria, Kavita Rawat, Balawant Kumar |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Protein Kinase C-alpha Immunoprecipitation viruses Two-hybrid screening Viral pathogenesis Receptor expression Mechanistic Target of Rapamycin Complex 2 Biology mTORC2 General Biochemistry Genetics and Molecular Biology Protein–protein interaction 03 medical and health sciences 0302 clinical medicine Antigens Neoplasm Serine Humans nef Gene Products Human Immunodeficiency Virus Phosphorylation General Pharmacology Toxicology and Pharmaceutics Caenorhabditis elegans Proteins Protein kinase B Macrophages virus diseases General Medicine Cell biology HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis Host-Pathogen Interactions HIV-1 Signal transduction Signal Transduction |
Zdroj: | Life Sciences. 214:158-166 |
ISSN: | 0024-3205 |
Popis: | Aims Human immunodeficiency virus −1 [HIV-1] Nef, localizes in different cellular compartments and modulates several cellular pathways. Nef promotes virus pathogenicity through alteration in cell surface receptor expression, apoptosis, protein trafficking etc. Nef regulates viral pathogenesis through interaction with different host proteins. Thus, molecular mechanisms of pathogenesis could be deciphered by identifying novel Nef interacting proteins. Main methods HIV-1 Nef interacting proteins were identified by pull down assay and MALDI-TOF analysis. The interaction was further validated through mammalian two hybrid assay. Functional role of this interaction was identified by immunoprecipitation assay, cell invasion and cell migration studies. Fold Change in mRNA levels of CD163, CD206, CCL17 and CCL18 was analyzed using qPCR. Key findings In current study, C. elegans protein ACT4C and its human homolog POTEE was identified to be interacting with Nef. This interaction activates mTORC2 complex, which in-turn activates AKT and PKC-α. The activation of mTORC2 complex was found to be initiated by the interaction of Nef, mTORC2, Rictor to POTEE. The cellular phenotype and functions affected by Nef-POTEE interaction resulted in significant increase in cell invasion and migration of macrophages (MΦ). Significance MΦ is primary target of HIV-1 infection where HIV-1 replicates and polarizes immunosuppressive M2 phenotype. Combine effect of M2 phenotype and Viral-host protein interactions compromise the MΦ associated physiological functions. Infected MΦ dissemination into other system also leads to HIV-1 induced malignancies. Therefore, targeting POTEE-Nef interaction can lead to formulating better therapeutic strategy against HIV-1. |
Databáze: | OpenAIRE |
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