TRIM5 retroviral restriction activity correlates with the ability to induce innate immune signaling

Host restriction factor TRIM5 inhibits retroviral transduction in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. But the restriction mechanism may not be that simple since TRIM5 E3 ubiquitin ligase activity, the proteasome, autophagy, and TAK1-dependent AP-1 signaling have been suggested to contribute to restriction. Here we show that, among a panel of seven primate and Carnivora TRIM5 orthologues, each of which has potential for potent retroviral restriction activity, all activated AP-1 signaling. In contrast, TRIM family paralogues most closely related to TRIM5 did not. While each primate species has a single TRIM5 gene, mice have at least seven TRIM5 homologues that cluster into two groups, Trim12a, b, and c, and Trim30a, b, c, and d. The three Trim12 proteins activated innate immune signaling, while the Trim30 proteins did not, though none of the murine Trim5 homologues restricted any of a panel of cloned retroviruses. To determine if any mouse TRIM5 homologues had potential for restriction activity each was fused to the HIV-1 CA binding protein cyclophilin A (CypA). The three Trim12-CypA fusions all activated AP-1 and restricted HIV-1 transduction, whereas the Trim30-CypA fusions did neither. AP-1 activation and HIV-1 restriction by the Trim12-CypA fusions was inhibited by disruption of TAK1. Overall then, these experiments demonstrate that there is a strong correlation between TRIM5 retroviral restriction activity and the ability to activate TAK1-dependent innate immune signaling. IMPORTANCE: The importance of retroviruses for the evolution of susceptible host organisms cannot be overestimated. 8% of the human genome is retrovirus sequence, fixed in the germline during past infection. Understanding how metazoa protect their genomes from mutagenic retrovirus infection is therefore of fundamental importance to biology. TRIM5 is a cellular protein that protects host genome integrity by disrupting the retroviral capsid as it transports viral nucleic acid to the host cell nucleus. Previous data suggest that innate immune signaling contributes to TRIM5-mediated restriction. Here we show that activation of innate immune signaling is conserved among primate and carnivore TRIM5 orthologues, and among 3 of the 7 mouse Trim5 homologues, and that such activity is required for TRIM5-mediated restriction activity

Biochemical and Molecular Bases of Lipid Metabolism in Hydra vulgaris

Here we have studied some biochemical and molecular characteristics of lipid metabolism in the Hydra cnidarian polyp. We have characterized variations in lipid metabolism in response to diet by establishing lipid profiles in starved and fed Hydra, and quantifying with the Red Nile technique the accumulation of lipid droplets in the digestive cells upon starvation. As expected, Hydra uses lipid reserves as fuel for survival, suggesting that fatty acids and cholesterol in the diet are esterified and stored when abundant and then released when fasting. During regeneration, specific classes of lipids appear to be needed, possibly for cell membrane synthesis and/or specific signalling. We finally identified five orthologs of the bilaterian genes encoding the dihydrolipoamide branched-chain transacylase (DBT), hydroxyacyl-CoA dehydrogenase (HCD), choline phosphotransefrase (CHPT), phosphatidylcholine Sterol-O acyltransferase (PCSAT) and lipophorin receptor /LDL (LpR/LDL). Phylogenetic analyses confirm that these enzymes and receptor essential for lipid metabolism are conserved in eumtazoans

Innate immune signaling and the contribution of different regions of capsid to HIV-1 restriction by TRIM5

The cellular factor TRIM5α performs a dual role in the innate immunity. First, TRIM5α has an intrinsic ability to induce the AP-1 and NFκB pathways and contributes to the establishment of the LPS-mediated antiviral state. Second, it functions as a restriction factor, blocking early stages of retroviral infection in a capsid-dependent manner. The connections between these two functions of TRIM5α are debated. We investigated the conservation, in TRIM5 orthologues, of the ability to activate the innate immune pathways and analyzed the signification of this function in the context of TRIM5- mediated HIV-1 restriction. We took the advantage that there are seven TRIM5 orthologues in the mouse, with variable abilities to activate the innate immune signaling, to determine the contribution of this signal activator function to the restriction process. [...

Files for mito-nuclear eQTLs analysis

Files that were used for mito-nuclear eQTL analyses.</p

A Bioinformatics View of Glycan–Virus Interactions

International audienceEvidence of the mediation of glycan molecules in the interaction between viruses and their hosts is accumulating and is now partially reflected in several online databases. Bioinformatics provides convenient and efficient means of searching, visualizing, comparing, and sometimes predicting, interactions in numerous and diverse molecular biology applications related to the-omics fields. As viromics is gaining momentum, bioinformatics support is increasingly needed. We propose a survey of the current resources for searching, visualizing, comparing, and possibly predicting host-virus interactions that integrate the presence and role of glycans. To the best of our knowledge, we have mapped the specialized and general-purpose databases with the appropriate focus. With an illustration of their potential usage, we also discuss the strong and weak points of the current bioinformatics landscape in the context of understanding viral infection and the immune response to it

TRIM5 is an innate immune sensor for the retrovirus capsid lattice

TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13-UEV1A (also known as UBE2N-UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13-UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice