SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation.

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

doi:10.1371/journal.pgen.1005367

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.

Highlights

SAM domain and HD domain containing protein 1 (SAMHD1) was first identified as an interferonγ-induced protein in macrophages and dendritic cells, and was regarded as a negative regulator of cellular innate immunity [1]
100 copies of long interspersed element 1 (LINE-1) are still active in an average individual genome
SAMHD1 was known for the association of its mutations with the Aicardi-Goutieres syndrome (AGS), a congenital autoimmune disease

Summary

Introduction

SAM domain and HD domain containing protein 1 (SAMHD1) was first identified as an interferonγ-induced protein in macrophages and dendritic cells, and was regarded as a negative regulator of cellular innate immunity [1]. As a deoxynucleotide triphosphate (dNTP) triphosphohydrolase, SAMHD1 is able to decrease dNTP level in non-cycling cells below the threshold that is required for DNA synthesis [4,5]. By virtue of this function, SAMHD1 inhibits a number of retroviruses and DNA viruses including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 1 (HSV-1) [6,7]. This mechanism of restriction is supported by the rescue of HIV-1 replication in SAMHD1-expressing cells with exogenous deoxynucleotides [8]. HIV-2 and certain strains of simian immunodeficiency virus (SIV) carry an auxiliary protein called Vpx that is able to direct SAMHD1 to the E3 ligase complex Cul4/CRL4/DCAF1 and causes SAMHD1 ubiquitination and subsequent proteasomal degradation [9,10,11,12,13,14,15,16,17]

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Results

Discussion

Conclusion