SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation

PLoS Genet. 2015 Jul 2;11(7):e1005367. doi: 10.1371/journal.pgen.1005367. eCollection 2015 Jul.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Proliferation / genetics
  • Cytoplasmic Granules / genetics*
  • DNA Helicases
  • Eukaryotic Initiation Factor-4G / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Long Interspersed Nucleotide Elements / genetics*
  • Monomeric GTP-Binding Proteins / genetics*
  • Phosphorylation
  • Poly(A)-Binding Proteins / metabolism
  • Poly-ADP-Ribose Binding 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
  • eIF-2 Kinase / metabolism

Substances

  • Carrier Proteins
  • EIF4G1 protein, human
  • Eukaryotic Initiation Factor-4G
  • Poly(A)-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • RNA, Small Interfering
  • T-Cell Intracellular Antigen-1
  • TIA1 protein, human
  • EIF2AK1 protein, human
  • eIF-2 Kinase
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases
  • Monomeric GTP-Binding Proteins

Grant support

This study was supported by funds from the Ministry of Science and Technology of China (2012CB911103; 2011CB5048002; 2012ZX10001006-003 and 2013ZX10001005-002) (FG), from the Nature Science Foundation of China (81371808 to FG; 81301439 to SH) and Canadian Institutes of Health Research (CCI-132561) (CL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.