SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation

Siqi Hu; Jian Li; Fengwen Xu; Shan Mei; Yann Le Duff; Lijuan Yin; Xiaojing Pang; Shan Cen; Qi Jin; Chen Liang; Fei Guo

doi:10.1371/journal.pgen.1005367

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.

Authors

Siqi Hu¹, Jian Li¹, Fengwen Xu¹, Shan Mei¹, Yann Le Duff², Lijuan Yin¹, Xiaojing Pang¹, Shan Cen³, Qi Jin¹, Chen Liang², Fei Guo¹

Affiliations

¹ MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.
² Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.

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

Grants and funding

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.