Abstract
TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition receptor (PRR) that activates inflammatory signaling. How TRIM5α carries out its multi-faceted actions in antiviral defense remains incompletely understood. Here, we show that proteins required for autophagy, a cellular self-digestion pathway, play an important role in TRIM5α's function as a PRR. Genetic depletion of proteins involved in all stages of the autophagy pathway prevented TRIM5α-driven expression of NF-κB and AP1 responsive genes. One of these genes is the preeminent antiviral cytokine interferon β (IFN-β), whose TRIM5-dependent expression was lost in cells lacking the autophagy proteins ATG7, BECN1, and ULK1. Moreover, we found that the ability of TRIM5α to stimulate IFN-β expression in response to recognition of a TRIM5α-restricted HIV-1 capsid mutant (P90A) was abrogated in cells lacking autophagy factors. Stimulation of human macrophage-like cells with the P90A virus protected them against subsequent infection with an otherwise resistant wild type HIV-1 in a manner requiring TRIM5α, BECN1, and ULK1. Mechanistically, TRIM5α was attenuated in its ability to activate the kinase TAK1 in autophagy deficient cells, and both BECN1 and ATG7 contributed to the assembly of TRIM5α-TAK1 complexes. These data demonstrate a non-canonical role for the autophagy machinery in assembling antiviral signaling complexes and in establishing a TRIM5α-dependent antiviral state.
Highlights
The selective pressure imposed by retroviral infection has shaped the human genome and has driven the evolution of proteins that function to protect host cells against retroviral infection [1]
We found that transient expression of both N-terminally and C-terminally tagged TRIM5 enhanced the relative expression of AP1-driven luciferase relative to cells expressing the tags alone (S1A Fig)
As was the case with the siRNA experiments, AP1 reporter expression was still induced by TRIM5 in the BECN1 and ATG7 knockout cells, albeit substantially less that what was seen in the control cells
Summary
The selective pressure imposed by retroviral infection has shaped the human genome and has driven the evolution of proteins that function to protect host cells against retroviral infection [1]. The ability of TRIM5 to restrict incoming retroviruses depends on whether or not the C-terminal PRY/SPRY domain of TRIM5 can recognize and bind to the retroviral capsid proteins in the context of an intact core structure These TRIM5-capsid interactions show a high degree of both host and viral species specificity, with human TRIM5 historically being considered unable to bind and restrict HIV-1 despite its ability to efficiently block infection by other retroviruses [3,4,5,6,7,8]. Despite TRIM5’s relative inability to protect human cells from HIV-1 infection in vitro, human genetic studies have indicated that certain TRIM5 alleles confer increased risk of HIV-1 infection in people [9,10,11] This implies that TRIM5 likely plays additional roles in antiretroviral defense beyond its actions in capsid-specific restriction (CSR)
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