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

Abstract

TRIM5 proteins mediate a potent block to the cross-species transmission of retroviruses, the most well known being the TRIM5␣ 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. TRIM5␣, as well as other TRIM family proteins, has been shown to be regulated by interferons (IFN). Here we show that TRIM5␣ 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 TRIM5␣ 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 TRIM5␣ cytoplasmic bodies and the level of TRIM5␣ protein expression were reduced in cell lines stably expressing epitope-tagged versions of TRIM5␣. In accordance with these data, p62 knockdown resulted in reduced TRIM5␣-mediated retroviral restriction in cells expressing epitope-tagged TRIM5␣ or expressing endogenously expressed human TRIM5␣. p62 may therefore operate to enhance TRIM5␣-mediated retroviral restriction, contributing to the antiviral state of cells following IFN treatment.

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

“…We found that the attachment of K48-linked polyubiquitin was largely p62-dependent, suggesting that PV-bound p62 recruits E3 ligases other than K63-specific TRAF6. We identified Trim21 as such a PV-resident E3 ligase that is known to interact with p62 and to form K48-linked polyubiquitin chains (52)(53)(54). Further defining the function of PVassociated E3 ligases such as Trim21 will doubtlessly reveal novel insights into host defense mechanisms directed at vacuolar pathogens.…”

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…Excitation light was generated using the Insight SSI solid-state illumination module (Applied Precision, GE), and images were deconvolved with the SoftWoRx deconvolution software (Applied Precision, GE). Following deconvolution, images were quantified by Imaris (Bitplane) software using the Surfaces feature function, generating surfaces around red puncta, as described (77). Three-dimensional views of images were generated using Surpass mode of Imaris software (78).…”

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

“…3A); the known examples include TRIM5 (O'Connor et al, 2010), TRIM50 , TRIM55 (Lange et al, 2005;Pizon et al, 2013;Mandell et al, 2014), TRIM13 (Tomar et al, 2012), TRIM17 and TRIM49 (Mandell et al, 2014), TRIM21 , as well as TRIM76 (Blandin et al, 2013). Furthermore, p62 can colocalize with TRIM63 in the cytoplasm and with TRIM19 in the nucleus within the nuclear PML bodies (Pankiv et al, 2010), although this might not be restricted to the nucleus because TRIM19 functions in the cytoplasm as well (Lin et al, 2004;Dutrieux et al, 2015).…”