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SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation
- Source :
- PLoS Genetics, PLoS Genetics, Vol 11, Iss 7, p e1005367 (2015)
- Publication Year :
- 2015
- Publisher :
- Public Library of Science (PLoS), 2015.
-
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.<br />Author Summary Long interspersed element 1 (LINE-1 or L1) comprises 17% of human genome, and has played a major role in shaping the evolution of human genome. Approximately 100 copies of LINE-1 are still active in an average individual genome. Movement of these LINE-1 sequences to new loci in the genome has the potential of causing sporadic cases of disease. Among the multi-layered mechanisms by which the host controls LINE-1 activity is a group of host restriction factors including APOBEC3 proteins. SAMHD1 was known for the association of its mutations with the Aicardi-Goutieres syndrome (AGS), a congenital autoimmune disease. SAMHD1 was recently reported as a host restriction factor that inhibits a number of retroviruses and DNA viruses including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 1 (HSV-1). Here, we demonstrate that SAMHD1 inhibits LINE-1 retrotransposition through promoting the sequestration of LINE-1 RNP within the cytoplasmic stress granules. SAMHD1 promotes the formation of large stress granules by inducing phosphorylation of eIF2α and disrupting eIF4A/eIF4G interaction. This is the first report describing the role of SAMHD1 in modulating the formation of stress granules. We envision that this function of SAMHD1 not only contributes to the inhibition of LINE-1, but also the restriction of various viruses.
- Subjects :
- Cancer Research
lcsh:QH426-470
Biology
Cytoplasmic Granules
Poly(A)-Binding Proteins
Cell Line
SAM Domain and HD Domain-Containing Protein 1
eIF-2 Kinase
03 medical and health sciences
0302 clinical medicine
Stress granule
Genetics
Humans
Stress granule assembly
Phosphorylation
RNA, Small Interfering
Poly-ADP-Ribose Binding Proteins
Molecular Biology
Genetics (clinical)
Ecology, Evolution, Behavior and Systematics
Cell Proliferation
Monomeric GTP-Binding Proteins
030304 developmental biology
0303 health sciences
EIF-2 kinase
HEK 293 cells
DNA Helicases
Transfection
T-Cell Intracellular Antigen-1
3. Good health
Cell biology
lcsh:Genetics
HEK293 Cells
Long Interspersed Nucleotide Elements
RNA Recognition Motif Proteins
030220 oncology & carcinogenesis
biology.protein
RNA Interference
Carrier Proteins
Eukaryotic Initiation Factor-4G
HD domain
RNA Helicases
Research Article
HeLa Cells
SAMHD1
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- PLOS Genetics
- Accession number :
- edsair.doi.dedup.....e944144d0c20ac9973d38c0df31b7cb4