Abstract
Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the reverse transcription step. In the present study, we sought to unravel the molecular mechanism of Daxx-mediated restriction and, in particular, to identify the protein(s) that Daxx targets in order to achieve its antiviral activity. First, we show that the SUMO-interacting motif (SIM) located at the C-terminus of the protein is strictly required for Daxx to inhibit HIV-1 reverse transcription. By performing a quantitative proteomic screen combined with classical biochemical analyses, we found that Daxx associated with incoming HIV-1 cores through a SIM-dependent interaction with cyclophilin A (CypA) and capsid (CA). Daxx was found to reside within a multiprotein complex associated with viral capsids, also containing TNPO3, TRIM5α, and TRIM34. Given the well-known influence of these cellular factors on the stability of HIV-1 cores, we investigated the effect of Daxx on the cytoplasmic fate of incoming cores and found that Daxx prevented HIV-1 uncoating in a SIM-dependent manner. Altogether, our findings suggest that, by recruiting TNPO3, TRIM5α, and TRIM34 and possibly other proteins onto incoming HIV-1 cores through a SIM-dependent interaction with CA-bound CypA, Daxx increases their stability, thus preventing uncoating and reverse transcription. Our study uncovers a previously unknown function of Daxx in the early steps of HIV-1 infection and further illustrates how reverse transcription and uncoating are two tightly interdependent processes.
Highlights
HIV-1, like all viruses, is an obligate parasite and requires numerous cellular factors and pathways to replicate
We previously reported that the Daxx protein inhibits HIV-1 replication by interfering with the reverse transcription step [40]
We first investigated whether Daxx was an Interferon-stimulated gene (ISG) product and whether it participated to the type I IFN-induced inhibition of HIV-1 reverse transcription [57,58]
Summary
HIV-1, like all viruses, is an obligate parasite and requires numerous cellular factors and pathways to replicate. Mammalian cells have developed specific factors that function in a cell-autonomous manner to limit virus replication. These have been termed restriction factors and constitute the so-called intrinsic immunity, which is considered to be the third arm of immunity [1]. Even if they are constitutively expressed, are upregulated by type I interferon(s), and intrinsic defenses can be considered to be a part of antiviral innate immunity [2,3]. Viruses 2020, 12, 636 in [5,6,7]). Reverse transcription appears to be a hotspot for restriction, since it is targeted by several potent antiviral factors, including TRIM5α [8], APOBEC3G [4,9], and SAMHD1 [10,11]
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