Dataset Information

Human TRIM5? senses and restricts LINE-1 elements.

ABSTRACT: 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 TRIM5? senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5? has been shown to efficiently block HIV-1 replication, while human TRIM5? was found to be less active. Surprisingly, we found that both human and rhesus TRIM5? efficiently repress human LINE-1 retrotransposition. TRIM5? 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 TRIM5? also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-?B, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5?, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5? 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.

SUBMITTER: Volkmann B

PROVIDER: S-EPMC7395565 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Human TRIM5α senses and restricts LINE-1 elements.

Volkmann Bianca B Wittmann Sabine S Lagisquet Justine J Deutschmann Janina J Eissmann Kristin K Ross James J JJ Biesinger Brigitte B Gramberg Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20200710 30

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 l ...[more]

PMID: 32651277

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Project description:Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5? was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5? is almost powerless to restrict HIV-1. However, human TRIM5? potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5? represents the restriction factor previously designated as Ref1. African green monkey TRIM5? represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5? is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5?. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between ?-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5? and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5? is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5?. Recently, human TRIM5? was shown to activate signaling pathways that lead to activation of NF-?B and AP-1 by interacting with TAK1 complex. TRIM5? is thus involved in control of viral infection in multiple ways.

Dataset Information

Human TRIM5? senses and restricts LINE-1 elements.

Publications

Human TRIM5α senses and restricts LINE-1 elements.

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