Endogenous TRIM5α Function Is Regulated by SUMOylation and Nuclear Sequestration for Efficient Innate Sensing in Dendritic Cells

Débora Portilho (1) , Juliette Fernandez (1) , Mathieu Ringeard (2) , Anthony K Machado (1) , Aude Boulay (1) , Martha Mayer (3) , Michaela Muller-Trutwin (4) , Anne-Sophie Beignon (5) , Frank Kirchhoff (3) , Sébastien Nisole (6, 7) , Nathalie Arhel (1)

1 Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales
2 Virologie moléculaire et Vectorologie
3 Universität Ulm - Ulm University [Ulm, Allemagne]
4 HIV, Inflammation et persistance - HIV, Inflammation and Persistence
5 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
6 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
7 UPD5 - Université Paris Descartes - Paris 5

During retroviral infection, viral capsids are subject to restriction by the cellular factor TRIM5α. Here, we show that dendritic cells (DCs) derived from human and non-human primate species lack efficient TRIM5α-mediated retroviral restriction. In DCs, endogenous TRIM5α accumulates in nuclear bodies (NB) that partly co-localize with Cajal bodies in a SUMOylation-dependent manner. Nuclear sequestration of TRIM5α allowed potent induction of type I interferon (IFN) responses during infection, mediated by sensing of reverse transcribed DNA by cGAS. Overexpression of TRIM5α or treatment with the SUMOylation inhibitor ginkgolic acid (GA) resulted in enforced cytoplasmic TRIM5α expression and restored efficient viral restriction but abrogated type I IFN production following infection. Our results suggest that there is an evolutionary trade-off specific to DCs in which restriction is minimized to maximize sensing. TRIM5α regulation via SUMOylation-dependent nuclear sequestration adds to our understanding of how restriction factors are regulated.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Microbiology and Parasitology; Virology; Life Sciences [q-bio]; Cellular Biology; Life Sciences [q-bio]; Immunology; Life Sciences [q-bio]; Immunology; Innate immunity

Débora Portilho, Juliette Fernandez, Mathieu Ringeard, Anthony K Machado, Aude Boulay, et al.. Endogenous TRIM5α Function Is Regulated by SUMOylation and Nuclear Sequestration for Efficient Innate Sensing in Dendritic Cells. Cell Reports, 2016, 14 (2), pp.355-369. ⟨10.1016/j.celrep.2015.12.039⟩. ⟨pasteur-01960638⟩