Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Abstract

It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the transGolgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. W ith worldwide seroprevalence rates reaching 60 to 90% (1), herpes simplex virus 1 (HSV-1) is a tremendously successful human pathogen. HSV-1 particles consist of a double-stranded DNA genome encased by an icosahedral capsid, surrounded by a proteinaceous layer known as the tegument, which is in turn enclosed by an envelope of host-derived lipids (2). During the lytic replication cycle, viral glycoprotein-mediated fusion of the envelope with the host cell plasma membrane releases the capsid and tegument proteins into the cytosol (3). HSV capsids are then transported to the nucleus along microtubules via molecular motor proteins (4). The release of the genome into the nucleus is followed by viral gene expression in a sequential manner, beginning with the immediate-early (IE) genes and then progressing to the early (E) and late (L) classes, resulting in viral genomic DNA replication and packaging into capsids.Although subsequent steps have been controversial, it is n...

Integrative Interactome and Ubiquitinome Analyses Reveal Multiple Regulatory Pathways Targeted by ICP0 in HSV-1 Infected Neuronal Cells

“…S1). Many previously reported ICP0 targets were also confirmed in these data, including viral proteins UL50 [32], UL39 [32] and RS1 (ICP4) [48,49] as well as host proteins USP7 [50], USP9X [31], PRKDC [51], DDX17 [52] and WDR11 [8]. Interestingly, eight proteins were found in all three cell lines: viral proteins UL50, UL39, RS1 and UL34, and host proteins USP7, USP9X, VIM and DBN1.…”

“…ICP0 is also a small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase, although not all its activity depends on SUMO modification [3,4]. ICP0 substrates have been reported to be involved in a wide range of host processes including intrinsic and innate immunity, chromatin remodeling and DNA damage response (DDR) pathways [5][6][7][8] (reviewed in [9][10][11]). For example, ICP0-induced degradation of PML leads to the disruption of PML nuclear bodies and release of entrapped viral genomes [12][13][14][15][16][17][18].…”

The WDR11 complex facilitates the tethering of AP-1-derived vesicles

“…WDR11 is a highly conserved protein but it is still relatively uncharacterised. Proposed functions include tumour suppression 10 , transcriptional regulation 11 , trafficking of endocytosed ricin 2 and control of viral assembly 12 . WDR11 has been reported to localise to the nucleus 11 , to autophagosomes 13 and to the TGN; 12 while proposed binding partners include the transcription factor EMX1 11 , the herpes simplex virus protein ICP0 12 and a protein of unknown function, C17orf75 13 .…”

Resveratrol reduced the detrimental effects of malondialdehyde on human endothelial cells

“…Meanwhile over activation of these genes stimulate different signaling pathways correlated with apoptosis and cell cycle. 45 Whether MDA acts differently in multiple genes belonging to each signal transduction pathway is the subject of debate. There are number of nuclear and cytoplasmic factor involved in the regulation of cell growth.…”