Abstract
Intrinsic immunity describes the set of recently discovered but poorly understood cellular mechanisms that specifically target viral pathogens. Their discovery derives in large part from intensive studies of HIV and SIV that revealed restriction factors acting at various stages of the retroviral life cycle. Recent studies indicate that some factors restrict both retroviruses and retrotransposons but surprisingly in ways that may differ. We screened known interferon-stimulated antiviral proteins previously untested for their effects on cell culture retrotransposition. Several factors, including BST2, ISG20, MAVS, MX2, and ZAP, showed strong L1 inhibition. We focused on ZAP (PARP13/ZC3HAV1), a zinc-finger protein that targets viruses of several families, including Retroviridae, Tiloviridae, and Togaviridae, and show that ZAP expression also strongly restricts retrotransposition in cell culture through loss of L1 RNA and ribonucleoprotein particle integrity. Association of ZAP with the L1 ribonucleoprotein particle is supported by co-immunoprecipitation and co-localization with ORF1p in cytoplasmic stress granules. We also used mass spectrometry to determine the protein components of the ZAP interactome, and identified many proteins that directly interact and colocalize with ZAP, including MOV10, an RNA helicase previously shown to suppress retrotransposons. The detection of a chaperonin complex, RNA degradation proteins, helicases, post-translational modifiers, and components of chromatin modifying complexes suggest mechanisms of ZAP anti-retroelement activity that function in the cytoplasm and perhaps also in the nucleus. The association of the ZAP ribonucleoprotein particle with many interferon-stimulated gene products indicates it may be a key player in the interferon response.
Highlights
Host restriction factor proteins are part of the intrinsic immune system of the cell, forming an early line of defense against viral infection
Retrotransposons are mobile double-stranded RNA binding protein Topoisomerase (DNA) elements that duplicate themselves by a "copy and paste" mechanism using an RNA intermediate
The cell has evolved defenses restricting retrotransposition, involving in some cases interferon-stimulated genes (ISGs) that are part of the innate immune system that protects the cell from viral infections
Summary
Host restriction factor proteins are part of the intrinsic immune system of the cell, forming an early line of defense against viral infection. Intrinsic immunity is triggered when viral RNAs are recognized by pattern-recognition receptors, such as Toll-like and retinoic acid-inducible gene (RIG-I)-like receptor family members, causing activation of an effector protein (for example, IRF3) and the expression of interferon (IFN) and hundreds of IFN-stimulated genes (ISGs). IFN-induced transmembrane protein family members (IFITM1/2/3) are potent inhibitors of a range of viruses including HIV-1, their mechanisms of action are unclear ([2]; reviewed in [3]). RSAD2 (Viperin) is an endoplasmic reticulum-associated protein that inhibits many RNA and DNA viruses at multiple stages of the viral life cycle, and which may be involved in innate immune signaling (reviewed in [5]). The transcriptional regulator TRIM28 (KAP1) limits HIV integration by binding acetylated integrase and inducing its deacetylation by recruiting HDAC1 [8]
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