SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation

• Published in: PLoS genetics Vol. 11; no. 7; p. e1005367
• Main Authors: Hu, Siqi, Li, Jian, Xu, Fengwen, Mei, Shan, Le Duff, Yann, Yin, Lijuan, Pang, Xiaojing, Cen, Shan, Jin, Qi, Liang, Chen, Guo, Fei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2015; Public Library of Science (PLoS)
• Subjects: Carrier Proteins - metabolism; Cell growth; Cell Line; Cell Proliferation - genetics; Cytoplasmic Granules - genetics; Deoxyribonucleic acid; DNA; DNA Helicases; eIF-2 Kinase - metabolism; Eukaryotic Initiation Factor-4G - metabolism; Experiments; Genetic testing; Genomes; HEK293 Cells; HeLa Cells; Herpes viruses; HIV; Human immunodeficiency virus; Humans; Kinases; Long Interspersed Nucleotide Elements - genetics; Lymphocytes; Medical research; Monomeric GTP-Binding Proteins - genetics; Phosphorylation; Poly(A)-Binding Proteins - metabolism; Poly-ADP-Ribose Binding Proteins; Proteins; RNA Helicases; RNA Interference; RNA Recognition Motif Proteins; RNA, Small Interfering; SAM Domain and HD Domain-Containing Protein 1; T-Cell Intracellular Antigen-1
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005367

The SAM domain and HD domain containing protein 1 (SAMHD1) inhibits retroviruses, DNA viruses and long interspersed element 1 (LINE-1). Given that in dividing cells, SAMHD1 loses its antiviral function yet still potently restricts LINE-1, we propose that, instead of blocking viral DNA synthesis by virtue of its dNTP triphosphohydrolase activity, SAMHD1 may exploit a different mechanism to control LINE-1. Here, we report a new activity of SAMHD1 in promoting cellular stress granule assembly, which correlates with increased phosphorylation of eIF2α and diminished eIF4A/eIF4G interaction. This function of SAMHD1 enhances sequestration of LINE-1 RNP in stress granules and consequent blockade to LINE-1 retrotransposition. In support of this new mechanism of action, depletion of stress granule marker proteins G3BP1 or TIA1 abrogates stress granule formation and overcomes SAMHD1 inhibition of LINE-1. Together, these data reveal a new mechanism for SAMHD1 to control LINE-1 by activating cellular stress granule pathway.