p62/Sequestosome-1 Associates with and Sustains the Expression of Retroviral Restriction Factor TRIM5α

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Abstract
TRIM5 proteins mediate a potent block to the cross-species transmission of retroviruses, the most well known being the TRIM5α protein from rhesus macaques, which potently inhibits human immunodeficiency virus type 1 (HIV-1) infection. This restriction occurs at an early stage in the replication cycle and is mediated by the binding of TRIM5 proteins to determinants present in the retroviral capsid. TRIM5α, as well as other TRIM family proteins, has been shown to be regulated by interferons (IFN). Here we show that TRIM5α associates with another IFN-induced gene, sequestosome-1/p62 (p62). p62 plays a role in several signal transduction cascades that are important for maintaining the antiviral state of cells. Here we demonstrate that p62 localizes to both human and rhesus macaque TRIM5α cytoplasmic bodies, and fluorescence resonance energy transfer (FRET) analysis demonstrates that these proteins closely associate in these structures. When p62 expression was knocked down via small interfering RNA (siRNA), the number of TRIM5α cytoplasmic bodies and the level of TRIM5α protein expression were reduced in cell lines stably expressing epitope-tagged versions of TRIM5α. In accordance with these data, p62 knockdown resulted in reduced TRIM5α-mediated retroviral restriction in cells expressing epitope-tagged TRIM5α or expressing endogenously expressed human TRIM5α. p62 may therefore operate to enhance TRIM5α-mediated retroviral restriction, contributing to the antiviral state of cells following IFN treatment.