Abstract
The post-entry restriction factor Trim5α blocks infection of retroviral pathogens shortly after the virus gains entry to the cell, preventing reverse transcription and integration into the host genome. Central to the mechanism of restriction is recognition of the lattice of capsid protein that forms the inner-shell of the retrovirus. To recognise this lattice, Trim5α has been shown to assemble into a large hexagonal array, complementary to the capsid lattice. Structures of the Trim5α coiled-coil region reveal an elongated anti-parallel dimer consistent with the edges of this array placing the Bbox domain at each end of the coiled-coil to facilitate assembly. To investigate the nature of this assembly we have designed and characterised a monomeric version of the TRIM RBCC motif with a truncated coiled-coil. Biophysical characterisation by SEC-MALLS, AUC, and SAXS demonstrate that this construct forms compact folded domain that assembles into a trimer that would support the formation of a hexagonal lattice. Furthermore, the RING domain and elements of the coiled-coil region are shown to contribute to assembly. Ubiquitylation assays demonstrate that this assembly increases ubiquitylation activity providing a link from recognition of the capsid lattice and assembly to the activation of innate immune signalling and restriction.
Highlights
Mammalian cells possess intrinsic defences against retroviral pathogens
Recognition of the intact capsid lattice is central to restriction of retroviral infection by Trim5α
While the C-terminal PRY/SPRY domain is responsible for direct recognition of the viral capsid protein, the functionality of the RBCC components are required for efficient restriction
Summary
Mammalian cells possess intrinsic defences against retroviral pathogens These responses to infection are facilitated by restriction factors that act during multiple stages of the retroviral life cycle to recognise, prevent, and contain infection. Such restriction factors include SamHD11, the Apobec[32] and Mx proteins[3], and members of the TRIM protein family. In addition to direct effects on the incoming virus Trim5αalso activates innate immune signalling via the production of ubiquitin chains This results in the activation of TAK1 and downstream inflammatory pathways. In this capacity Trim5αacts as a pattern recognition receptor for the assembled retroviral capsid[9]. To investigate the nature of this assembly and the interactions that govern its formation we have undertaken a structural and biophysical approach, examining the self-association of Trim5αto characterise the interfaces that are required for the assembly
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