Stress out the LINEs

Abstract

Occupying 17% of human genome, the mobile long interspersed element 1 (LINE-1 or L1) continues to modulate the landscape of our genome by inserting into new loci and, as a result, causing sporadic diseases. It is not surprising that human cells have evolved a battery of mechanisms to control and limit the activity of LINE-1. Our recent study unravels such a mechanism that is imposed by the stress granule pathway. This mechanism functions by sequestering the LINE-1 RNA-protein complex within the cytoplasmic stress granules and thus inhibiting the nuclear import of LINE-1 RNA and its subsequent reverse transcription and integration into cellular DNA. Conditions that promote stress granule formation, such as expression of the SAMHD1 protein, further reduce LINE-1 retrotransposition.

Keywords: LINE-1; SAMHD1; host restriction; retrotransposition; stress granule.

Figure 1.

Restriction of LINE-1 by SAMHD1 and stress granules. LINE-1 ORF1p and ORF2p associate with LINE-1 RNA and together form RNP complexes. LINE-1 RNP complexes enter the nucleus where LINE-1 RNA is reverse transcribed into DNA by a target-primed mechanism. Formation of stress granules is stimulated by eIF2α phosphorylation that is catalyzed by different kinases that are activated in response to different types of stresses. The LINE-1 restriction factors including G3BP1, TIA1, ZAP, PABP, APOBEC and MOV10 are co-localized with LINE-1 RNP in stress granules or P-bodies. Stress granules appear to serve as the cytoplasmic structure where LINE-1 RNP is sequestered in association with anti-LINE-1 factors that together achieve the maximal control of LINE-1. SAMHD1 enhances stress granules formation via modulating the phosphorylation of eIF2α by mechanisms to be elucidated.