title: The eukaryotic elongation factor eEF1A1 interacts with SAMHD1.
abstract: Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), a Mendelian inflammatory disease which displays remarkable clinical and biochemical overlap with congenital viral infection. SAMHD1 (SAM domain and HD domain-containing protein 1) has also been defined as an HIV-1 restriction-factor that, through a novel triphosphohydrolase activity, inhibits early stage HIV-1 replication in myeloid-derived dendritic cells (MDDCs), macrophages and resting CD4+ T-cells. The potent activity of SAMHD1 is likely to be the subject of a variety of regulatory mechanisms. Knowledge of proteins that interact with SAMHD1 may not only enhance our understanding of the pathogenesis of AGS, but may also provide further details on the link between the regulation of cellular dNTPs and HIV-1 restriction. In the present study, we used a yeast two-hybrid screen and pull-down analysis followed by MS to identify the eukaryotic elongation factor 1A1 (eEF1A1) as a potential interaction partner of SAMHD1. This interaction was confirmed by unbiased co-immunoprecipitation and demonstrated in situ by a proximity ligation assay (PLA). We show that this interaction is enhanced in mutant SAMHD1 cell lines and suggest that eEF1A1 may mediate SAMHD1 turnover by targeting it to the proteosome for degradation through association with Cullin4A and Rbx1.
authors.affiliation: *Genetic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, Manchester M13 9PT, U.K.
authors.forename: Catherine
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: †Division of Molecular Structure, MRC National Institute for Medical Research, the Ridgeway, Mill Hill, London NM7 1AA, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Schwefel
authors.affiliation: †Division of Molecular Structure, MRC National Institute for Medical Research, the Ridgeway, Mill Hill, London NM7 1AA, U.K.
authors.forename: Valerie
authors.initials: V
authors.lastname: Ennis-Adeniran
authors.affiliation: †Division of Molecular Structure, MRC National Institute for Medical Research, the Ridgeway, Mill Hill, London NM7 1AA, U.K.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Taylor
authors.affiliation: *Genetic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, Manchester M13 9PT, U.K.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: *Genetic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, Manchester M13 9PT, U.K.
authors.forename: Michelle
authors.initials: M
authors.lastname: Webb
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015398:Signal Transduction; D061805:Transcription Elongation, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C094814:EEF1A1 protein, human; D020648:Peptide Elongation Factor 1; C479529:RBX1 protein, human; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D046988:Proteasome Endopeptidase Complex; D020559:Monomeric GTP-Binding Proteins