Human TRIM5α senses and restricts LINE-1 elements

Abstract

<jats:p>Mobile genetic elements have significantly shaped our genomic landscape. LINE-1 retroelements are the only autonomously active elements left in the human genome. Since new insertions can have detrimental consequences, cells need to efficiently control LINE-1 retrotransposition. Here, we demonstrate that the intrinsic immune factor TRIM5α senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5α has been shown to efficiently block HIV-1 replication, while human TRIM5α was found to be less active. Surprisingly, we found that both human and rhesus TRIM5α efficiently repress human LINE-1 retrotransposition. TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In line with its postulated role as pattern recognition receptor, we show that TRIM5α also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-κB, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5α, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5α as pattern recognition receptor and shed light on its previously undescribed activity against mobile genetic elements, such as LINE-1, to protect the integrity of our genome.</jats:p>

Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning

“…These recent studies further underline the capacity of huTRIM5α to potentially restrict HIV-1 in other relevant human target cells such as DCs, CD4 + T cells, and macrophages. Thus, efficient huTRIM5α restriction likely depends on TRIM5α subcellular localization (e.g., nucleus versus cytosol) within specific cell or tissue types, but also on the ability to induce autophagy- and immunoproteasome-facilitated degradation pathways, the presence of additional cellular factors that facilitate the action of huTRIM5α (e.g., Langerin), and the absence or inhibition of cellular factors that block huTRIM5α recognition of the viral capsid (e.g., CypA) [ 62 , 64 , 65 , 186 ].…”

“…In addition to huTRIM5α sensing of exogenous retroviruses such as HIV-1, recent data suggest that the hypothesis that TRIM5α evolution was driven by retroelements, or endogenous retroviruses, is well-founded [ 186 , 198 , 199 ]. Notably, huTRIM5α was shown to both sense and restrict LINE-1 transposable elements, the only known autonomously active transposable element in humans, in HEK 293T cells [ 186 ]. Functional SPRY and B-box domains were essential for huTRIM5α-mediated inhibition of LINE-1 replication and insertion into the host genome.…”

“…Cytoplasmic co-localization of huTRIM5α and LINE-1 ribonucleoproteins (RNPs), in either cytoplasmic bodies or in a more diffuse pattern, was necessary for huTRIM5α-mediated LINE-1 restriction. In addition, upon sensing LINE-1 RNPs, huTRIM5α activated the TAK1 kinase complex, leading to subsequent activation of the AP-1 and NF-κB pathways [ 186 ]. Furthermore, rhTRIMCyp also inhibited LINE-1 retrotransposition, suggesting that, as with the SPRY domain of huTRIM5α, CypA may also bind LINE-1 RNPs leading to retroelement restriction.…”

Recognize Yourself—Innate Sensing of Non-LTR Retrotransposons

“…Recently, we identified a novel retroelement-specific trigger of innate immune signaling. Our study demonstrated that the intrinsic restriction factor human tripartite motif-containing 5α (TRIM5α) senses and inhibits LINE-1 retrotransposition [ 109 ]. Previously, TRIM5 proteins have been shown to restrict exogenous retroviruses in a species-specific manner (reviewed in [ 110 ]).…”

“…The signaling events activate the transcription factors AP-1 and NF-κB, leading to the downregulation of LINE-1 promoter activity, most likely indirectly by activating additional inhibitory factors. Together, we identified LINE-1 as target of TRIM5α, which restricts and senses LINE-1 RNPs in the cytoplasm, leading to inactivation of its promotor via a negative feedback loop, thereby protecting the genome from excess LINE-1 activity [ 109 ].…”